Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1 -- 4432 2023-09-05 23:00:24 |
2 only format change -9 word(s) 4423 2023-09-07 04:57:34 |

Video Upload Options

Do you have a full video?

Confirm

Are you sure to Delete?
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Poledniczek, M.; Neumayer, C.; Kopp, C.W.; Schlager, O.; Gremmel, T.; Jozkowicz, A.; Gschwandtner, M.E.; Koppensteiner, R.; Wadowski, P.P. Pathophysiology of Inflammation in Peripheral Artery Disease. Encyclopedia. Available online: https://encyclopedia.pub/entry/48857 (accessed on 14 June 2024).
Poledniczek M, Neumayer C, Kopp CW, Schlager O, Gremmel T, Jozkowicz A, et al. Pathophysiology of Inflammation in Peripheral Artery Disease. Encyclopedia. Available at: https://encyclopedia.pub/entry/48857. Accessed June 14, 2024.
Poledniczek, Michael, Christoph Neumayer, Christoph W. Kopp, Oliver Schlager, Thomas Gremmel, Alicja Jozkowicz, Michael E. Gschwandtner, Renate Koppensteiner, Patricia P. Wadowski. "Pathophysiology of Inflammation in Peripheral Artery Disease" Encyclopedia, https://encyclopedia.pub/entry/48857 (accessed June 14, 2024).
Poledniczek, M., Neumayer, C., Kopp, C.W., Schlager, O., Gremmel, T., Jozkowicz, A., Gschwandtner, M.E., Koppensteiner, R., & Wadowski, P.P. (2023, September 05). Pathophysiology of Inflammation in Peripheral Artery Disease. In Encyclopedia. https://encyclopedia.pub/entry/48857
Poledniczek, Michael, et al. "Pathophysiology of Inflammation in Peripheral Artery Disease." Encyclopedia. Web. 05 September, 2023.
Pathophysiology of Inflammation in Peripheral Artery Disease
Edit

Inflammation has a critical role in the development and progression of atherosclerosis. On the molecular level, inflammatory pathways negatively impact endothelial barrier properties and thus, tissue homeostasis. Conformational changes and destruction of the glycocalyx further promote pro-inflammatory pathways also contributing to pro-coagulability and a prothrombotic state. In addition, changes in the extracellular matrix composition lead to (peri-)vascular remodelling and alterations of the vessel wall, e.g., aneurysm formation. Moreover, progressive fibrosis leads to reduced tissue perfusion due to loss of functional capillaries.

atherosclerosis inflammation peripheral artery disease glycocalyx endothelial dysfunction

1. Introduction

Cardiovascular disease (CVD) is the leading cause of mortality worldwide and accounts for millions of deaths globally [1]. CVD is associated with a significant impairment of quality of life and the prevalence of its main manifestations, such as coronary artery disease (CAD), cerebrovascular disease and peripheral artery disease (PAD), has been increasing steadily over the last two decades [1][2].
Atherosclerosis is considered the major driver of CVD. Formerly, atherosclerosis was thought of as a process primarily related to dyslipidaemia and the deposition of triglycerides and cholesterol [3]. However, besides lipid accumulation, more recent insights into the pathogenesis of atherosclerosis increasingly emphasise the role of inflammation and endothelial dysfunction as major drivers of atherogenesis [3][4][5][6][7][8]. Moreover, the mentioned pathomechanisms depend on each other and amplify each other’s responses. Indeed, a central element initiating prothrombotic processes and herein, atherogenesis, remains glycocalyx destruction due to inflammatory processes [9]. In PAD, inflammation is also triggered by ischaemia-reperfusion (I/R) injury promoting increased production of reactive oxygen species (ROS) [10], which contribute to endothelial dysfunction and microvascular pathology [11].
Chronic autoimmune diseases, which are associated with significantly elevated levels of systemic inflammation, e.g., rheumatoid arthritis, systemic lupus erythematosus, anti-phospholipid syndrome and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), are associated with markedly increased prevalence of CVD [12][13][14]. Conversely, there is accumulating evidence that some agents with anti-inflammatory characteristics reduce cardiovascular risk significantly [15][16]. Canakinumab, a monoclonal antibody targeting interleukin (IL)-1β [15], and colchicine, which attenuates leukocyte responsiveness by inhibition of tubulin polymerisation [16][17], have been shown to improve outcomes in CAD in randomized controlled trials [15][16]. While not yet implemented in regular clinical practice, there is increasing awareness for anti-inflammatory therapy in secondary prevention of CVD in the current guidelines [18].
The single most effective prevention of CVD, smoking cessation, lowers levels of systemic inflammation as assessed utilising biomarkers of inflammation and oxidative damage [19][20]. Statins, which are the most widely established agents for lipid control, also have been shown to exert significant immuno-modulatory influence by inhibiting the nuclear factor kappa B (NF-ĸB) pathway and decreasing the expression of toll-like receptors (TLR) [21]. Smoking cessation and statins are both recommended in all patients with CVD [22].
Formation of aneurysms is also considered to be linked to atherosclerosis. Recently, the role of leukocytes and, especially, neutrophils in the development of aneurysms has been revisited [23][24]. Activation of matrix metalloproteinases (MMP), degradation of the extracellular matrix (ECM), smooth muscle apoptosis and oxidative stress all contribute to aneurysm formation and are mediated by cytokines secreted by leukocytes [23][25]. Interestingly, atherosclerosis and aneurysm formation do not always occur at the same locations. While the abdominal aorta, an area of predilection for aneurysm formation, is also prone to atherosclerosis, the external iliac artery, a common location for significant atherosclerosis, is very seldomly involved in the formation of aneurysms. Which cellular and non-cellular processes discern these two locations is currently unclear, however, the different embryologic origin of these vessels may be responsible for varying susceptibility to atherosclerosis and aneurysm formation, respectively [24].

2. Pathophysiology

2.1. Inflammation and Endothelial Dysfunction

Endothelial and vessel homeostasis is to a wide extent ensured by an intact glycocalyx coverage [26]. The endothelial glycocalyx is located at the luminal side of the cells and consists of membrane-bound proteoglycans and, together with adsorbed proteins, forms the endothelial surface layer [27]. Its components exert significant influence on the interactions between the blood and the endothelium, including rolling and diapedesis of leukocytes [28], platelet adhesion and activation [29], interaction with pro-coagulatory proteins [27], endothelial permeability [30] and the regulation of vascular tone [31].
Dysfunction and degradation of the endothelial glycocalyx allows low-density lipoproteins (LDLs) to accumulate in the endothelial wall [32]. Following aggregation, LDL is oxidised (oxLDL) and subsequently phagocytosed by macrophages, which transform into foam cells and thereby initiate the progressive process of atherogenesis [32]. In turn, the integrity of the endothelial glycocalyx is disturbed by vascular inflammation, therefore creating a vicious cycle of endothelial dysfunction, inflammation and progression of atherosclerosis [33].
The components of the glycocalyx also play a major role in the modulation of thromboinflammatory pathways [9][34]. Importantly, the glycocalyx barrier does not only cover endothelial cells, but functions as a protective barrier exhibiting steric and charge hindrance on blood components such as macrophages, erythrocytes, microspheres, tumour cells and microbes [35][36]. Similarly, neutrophils have been demonstrated to express syndecan-1 and syndecan-4, hyaluronan, serglycin and cluster of differentiation (CD) 44 in their surface layer [37]. These molecules are essential components of both the endothelial and the neutrophil surface layers and are thought to regulate neutrophil rolling and recruitment [37]. Modifications to the neutrophil surface layer, including shedding of the glycocalyx and formation of microvilli, are thought to regulate leukocyte behaviour by exposing receptor proteins and promoting leukocyte activation [36][38]. However, the exact interactions of the endothelial and the neutrophil surface layers remain to be completely elucidated [37].
Macrophage activation after phagocytosis may lead to macrophage extracellular trap (MET) formation, but the process might be dependent on the recognized pathogen [39][40]. On the other hand, inflammation triggers leukocyte activation, promoting neutrophil– and monocyte–platelet aggregate formation [41][42]. The process is perpetuated by ETosis and enhanced oxidative stress [43][44][45].
Moreover, activated platelets lead to a thrombin burst; thrombin is the strongest platelet agonist, mediating platelet activation via protease-activated receptors (PARs) 1 and 4 at subnanomolar concentrations [46]. Platelet aggregation through these pathways has been shown to be preserved despite adequate dual P2Y12 inhibition in patients with acute coronary syndromes [47]. Moreover, thrombin also activates platelets via glycoprotein Ib [48]. Further, inflammation mediates platelet activation through other alternative signalling pathways, including damage-associated signalling through TLRs [34]. Human platelets express all 10 TLR receptors [49], and related inflammatory signalling leads, amongst others, to P-selectin expression, ROS formation and enhanced platelet–neutrophil contacts [50]. Moreover, TLR-induced endothelial activation results in endothelial dysfunction [51]. The complex interplay of TLR receptor signalling pathways leads through signalling cascades via toll-interleukin-1 receptor resistance (TIR) domain-containing adaptor proteins to gene expression altering via different transcription factors, such as nuclear factor-κB (NF-κB), activator protein 1 (AP-1), nuclear factor erythroid-2-related factor 2 (NRF2), activating transcription factor 2 (ATF2) and interferon regulatory factors (IRFs) [34]. In humans, there are five TIR adaptors, namely the myeloid differentiation primary response protein 88 (MyD88), TIR domain-containing adaptor protein (TIRAP), TRIF, TRIF-related adaptor molecule (TRAM) and TIR domain sterile alpha and HEAT/Armadillo motif (SARM) [34][52][53][54][55].
All human TLRs signal via MyD88 to mediate inflammatory cytokine production [56][57]. However, NF-κB and the IRFs can be activated via MyD88-dependent, as well as MyD88-independent, pathways [53][58][59]. TLR-induced NF-κB activation modulates the NLRP3 inflammasome, which is a major mediator of IL-1 family cytokine production [60][61]. NLRP3 activation is directly involved in endothelial dysfunction, and enhanced expression was found in the serum of PAD patients [62][63].
TLR-4-mediated signalling in platelets, neutrophils and macrophages also contributes to neutrophil extracellular trap (NET) and MET formation, respectively [64][65][66][67].
Some risk factors commonly associated with atherosclerosis and thromboembolic events are also thought to impair the integrity of the glycocalyx [33]. Chronic diseases, such as diabetes mellitus (DM) and chronic kidney disease, are often linked to inflammatory processes and promote glycocalyx disturbance [33][68][69][70][71][72][73][74].
Several pathophysiologic properties link atherosclerosis and DM [75]. First, DM-associated dyslipidaemia leads to increased triglyceride-rich lipoproteins (TLP) in serum [75]. Under physiologic circumstances, insulin regulates hepatic lipoprotein and triglyceride production, however, in DM, these regulatory properties are diminished due to hepatic insulin resistance [75]. It has been demonstrated that not only the prevalence of lipoproteins, but also their modifications, can be considered essential for atherogenesis [76]. In a murine model of DM, an injection of LDL from diabetic patients resulted in a fourfold increase in arterial wall LDL retention compared to injected LDL from clinically healthy, non-diabetic control subjects [76].
Advanced glycation end-products (AGEs) are formed in patients with prolonged hyperglycaemia by non-enzymatic post-translational modification of proteins, lipids and nucleic acids [77]. AGEs promote inflammation by facilitating the activation of the endothelium, increasing cytokine release from macrophages, and ultimately, enhancing ROS production [10]. The latter are also key in I/R injury in PAD and contribute to inflammatory processes and endothelial dysfunction [10]. Ischaemia leads to succinate accumulation due to impaired mitochondrial citric acid cycle (TCA) [78][79]. Succinate can be transported to the cytosol, where, due to its excess, it leads to prolyl hydroxylase activity impairment and, in turn, to the stabilization and activation of the transcription factor hypoxia-inducible factor 1 (HIF-1) α. This pathway results in the expression of IL-1ß [80]. In addition, succinate accumulation is a hallmark of macrophage polarisation, occurring in the pro-inflammatory M1 macrophages [81].
Reperfusion leads to rapid reoxidation of succinate by succinate dehydrogenase, driving extensive ROS generation [82]. During I/R injury, NO bioavailability is decreased, and ROS activate the nucleotide oligomerization domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasomes, promote mitochondrial fission and endothelial microvesicle release, and change connexin/pannexin signalling [11]. As a result of the oxidative stress, I/R impairs capillary perfusion [11]. Furthermore, reduced NO levels promote M1 polarisation [83].
CVD including PAD is further linked to a reduced endothelial progenitor cell (EPC) number [84]. The inflammatory processes induced by uncontrolled oxidative stress also modify EPC function and thus impair endothelial regenerative potential [85]. In response to ischaemia, EPC release has been demonstrated to be markedly decreased in patients with PAD compared to healthy control subjects [86]. After mobilization, EPCs were shown to home to ischaemic tissue, facilitated by vascular growth factor (VEGF) and stromal cell-derived factor 1 (SDF-1) [87]. The latter binds to C-X-C chemokine receptor type 4 (CXCR-4) on EPCs [88].
EPCs have been shown to express gene transcripts coding for TLR 1–6, including the TLR-4 co-receptor CD14, TLR 8–10 and the TLR adaptor molecule myeloid differentiation factor 88 (MyD88) [89]. Hence, during inflammation, EPCs might also be modulated by TLR signalling pathways, such as TLR-4 mediated caspase 3 signalling promoting EPC apoptosis [85][90]. In addition, ROS formation triggers extracellular trap formation by different cells of the immune system such as neutrophils, eosinophiles, macrophages and mast cells, hereby influencing coagulability and vascular perfusion [34][91].
Coronavirus disease 2019 (COVID-19), which increases the risk of thromboembolic events during and after the infection [92], is also thought to impair the regular functioning of the glycocalyx [9][93][94]. The degradation of the glycocalyx is mediated by a complex interaction of cellular and non-cellular factors but is mainly driven by infection of endothelial cells by severe acute respiratory distress syndrome coronavirus type 2 (SARS-CoV-2) [95]. Subsequent endothelial inflammation and damage leads to disintegration of the glycocalyx, collagen exposure and, thereupon, activation of leukocytes and platelets [96]. These processes are thought to lead to an environment of thromboinflammation, which may ultimately trigger atherogenic processes and promote organ dysfunction [9][94].

2.2. Microparticles

Microparticles (MP) are cell-membrane-derived vesicles which are shed by, among others, endothelial cells, leukocytes, monocytes and platelets [97] at an increased rate upon cell activation due to oxidative injury, shear stress and apoptosis [98]. MPs can carry a plethora of cell-specific proteins and molecules such as receptors, lipids and both mitochondrial desoxyribonucleic acid (DNA) and messenger ribonucleic acid (mRNA) [97]. MPs are thought to contribute to cell–cell communication as their surface is representative of the originator cell [97][99][100]. Novel diagnostic and therapeutic applications are currently under investigation and first results seem promising [101]. MP composition has been demonstrated to be altered in inflammatory conditions, where endothelial cells stimulated with tumour necrosis factor (TNF)-α secrete MPs rich in pro-inflammatory cytokines and chemokines [102]. Intercellular signalling via MPs is therefore considered to exert a significant regulatory role in vascular homeostasis [103][104].
Under physiologic conditions, endothelial nitric oxide (NO) synthetase maintains vascular homeostasis by regulation of vascular tone and inhibition of platelet function through NO [105]. In addition, NO promotes anti-inflammatory M2 macrophage polarisation and limits the pro-inflammatory M1 phenotype [83]. In conditions associated with CVD, e.g., hypertension, tobacco abuse and dyslipidaemia, the endothelial production of NO is drastically reduced, leading to increased platelet activation and leukocyte diapedesis [105][106][107].
As described above, endothelial dysfunction is generally considered the earliest stage of atherogenesis [108]. While at physiological levels, ROS serve as signalling molecules with effects on cell differentiation, growth and apoptosis, in higher levels, their ability to oxidise various molecules results in cellular dysfunction and inflammation [109][110]. Under normal conditions, ROS are generated by mitochondria in the course of the electron transport chain, by xanthin oxidase and uncoupled endothelial NO synthetase (eNOS), and by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase [110]. The latter is especially important as a source of ROS in host-defence responses and inflammation [109].
ROS trigger a range of cellular responses, which include the activation of the NLRP3 inflammasome and consecutive IL-1β activation, the inhibition of eNOS via peroxisome proliferator-activated receptor (PPAR)-γ and adenosine-monophosphate-kinase (AMPK), and increased expression of adhesion molecules and several pro-inflammatory cytokines [110][111][112]. ROS have also been demonstrated to activate the TLR-4-mediated NF-ĸB signalling pathway [113] and, therefore, stimulate further ROS formation [110][114]. In addition, MPs also bind to TLR-4, and can induce NLRP3 inflammasome activation and IL-1ß expression through phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signalling [115]. By binding to TLR-4 on platelets, MPs also contribute to platelet activation [116].
Furthermore, MPs can aggravate ROS production by expressing NADPH oxidase [117][118], potentially creating a vicious cycle of self-sustained pro-atherogenic stimuli. Importantly, MPs can not only induce the release of pro-inflammatory cytokines and ROS, but can in fact act as a vehicle of transfer between donor and recipient cells, conferring both pro- as well as anti-inflammatory effects [119].
In particular, MPs derived from endothelial cells (EMP) and platelets (PMP) disrupt endothelial function and impair endothelium-induced vasodilation [120][121]. Formation of EMPs has been shown to correlate with carotid artery atherosclerotic plaque size in patients recovering from stroke [122] and promote inflammation [123]. Via regulation of macrophage functions, adipose-tissue-derived MPs facilitate foam cell formation, herein being central in the progression of atherosclerosis [124].
Depending on the donor cell and its state of activation, MPs express and transfer specific microRNAs (miRNA), which are thought to contribute to intercellular signalling [125][126][127][128][129]. miRNAs are single-stranded non-coding RNAs of up to 25 nucleotides, which bind to miRNA-response elements in untranslated regions of target genes, therefore regulating gene expression [130][131]. miRNA can also be found in plasma bound to proteins, such as argonaute 2 and high-density lipoprotein (HDL) [132][133].
Signalling via miRNA has been demonstrated to exert both pro- as well as anti-atherogenic effects on target cells and to regulate vascular inflammation, the formation of a neointima following stent implantation and endothelial regeneration [125][134][135]. In the context of cigarette smoking and PAD, the downregulation of miRNA-27b is independently associated with tobacco abuse and severity of PAD [128]. Following endovascular angioplasty and stent implantation for PAD, miRNA-195 has been found to predict adverse ischaemic events and the need for target vessel revascularisation [134].
In another study, miRNA-30c-5p was shown to inversely correlate with levels of LDL and plaque development, while miRNA-30c-5p expression in MPs was inhibited via the scavenger receptor CD36 by oxLDL and, in turn, modulated macrophage IL-1β release, caspase 3 and apoptosis [127]. Furthermore, miRNA-21 and miRNA-126 have also been independently associated with monocyte–platelet aggregate formation in acute coronary syndrome patients in vivo, as well as after TLR 1/2 activation [136]. In patients with CAD, MP miRNA enrichment and function was demonstrated to be impaired, which may contribute to disease progression [137]. Conversely, in an animal model of atherosclerosis, the incorporation of MPs of healthy controls resulted in improved EPC function due to miRNA transfer (miRNA-10a, miRNA-21, miRNA-126, miRNA-146a and miRNA-223) [138].

2.3. Neutrophil Extracellular Traps

Neutrophil extracellular traps (NETs)—web-like structures consisting of cell-free DNA—are extruded from neutrophils upon activation during inflammatory processes and consist of chromatin, histones and neutrophil granule proteins [139][140]. Previously, NETosis, which describes the process of neutrophils releasing NETs, was primarily regarded as a mechanism of the innate immune system to engulf and neutralise a wide range of extracellular pathogens including bacteria [139], viruses [141] and fungi [141]. However, NETosis is suggested to play a crucial role in inflammatory diseases including vasculitis [142], atherosclerosis and thrombosis [143].
There is increasing evidence that NETs contribute to endothelial dysfunction [144][145], glycocalyx degradation [9] and atherosclerosis [143] by generation of ROS and concomitant release of neutrophil granule proteins associated with atherogenesis, including neutrophil elastase and myeloperoxidase [146][147]. Vice versa, both enzymes also play a crucial role in the induction of NETosis [148][149]. Moreover, ROS stimulate the formation of pro-inflammatory MPs [150].
In atherosclerosis, oxLDL is also a potent stimulus for NET formation. Awasthi et al. have shown that incubation of neutrophils with oxLDL leads to NETosis in a time- and concentration-dependent manner [151]. OxLDL is likely to induce NETosis via TLR-2 and TLR-6, as their blockade resulted in significantly reduced NETosis [151]. Furthermore, the recognition of NETs promotes the production of an IL-1β precursor in macrophages and the subsequent release of mature IL-1β upon phagocytosis of oxLDL [152]. This, in turn, causes IL-17 production from T-cells [152]; IL-17 is a potent chemokine perpetuating the pro-atherogenic inflammatory environment [152]. In addition, oxidative stress induced by NET-associated enzymes, including myeloperoxidase and NO synthetase, is considered to promote oxidation of HDL, therefore rendering this inherently anti-atherosclerotic protein dysfunctional [153].
From a clinical perspective, NETs also offer relevant insight into the mechanisms of atherothrombosis [154][155]. Activated neutrophils and NETs were detected in about 90% of thrombi from patients with acute myocardial infarction and NET load correlated with infarct size and resolution of ST-segment elevation [155].

2.4. The Role of Inflammation in Aneurysm Formation

The most common location of aortic aneurysms is the infrarenal segment of the abdominal aorta [156]. While often asymptomatic, abdominal aortic aneurysms (AAA) are associated with significant mortality. In the UK, ruptured AAAs account for 7.5 and 3.7 deaths per 100.000 for men and women, respectively, while in the Mediterranean, these numbers are closer to 1.0–2.8 per 100.000 per year [157].
The presence of leukocytes [158][159], enzymes degrading ECM in the aortic wall [160][161] and excessive levels of inflammatory parameters [25] have been reported hallmarks of aneurysm formation. The risk factors associated with aneurysm formation are similar to those for atherosclerosis, namely, among others, male sex, dyslipidaemia and tobacco use [162][163].
While DM is a common risk factor for atherogenesis [22], it is associated with a reduction of morbidity due to AAA by almost a third [164]. DM enhances atherosclerosis progression and vascular calcification [165][166]. The latter accounts for a higher cardiovascular risk and higher mortality in diabetic patients and those with chronic kidney disease [167][168].
The observed survival benefit in diabetic patients with AAA is not yet fully elucidated and may be attributed towards DM itself or concomitant metformin therapy [169], as randomised placebo-controlled trials investigating metformin-repurposing for the prevention of AAA formation and enlargement are still ongoing [170][171][172]. Furthermore, increased vascular calcification is linked to aortic aneurysmal wall stabilization and slower AAA progression [173].
The estimated rate of comorbidity of atherosclerosis and aneurysm formation is about 27–53% [174][175]. Atherosclerosis and aneurysm formation are both increasingly regarded as inflammatory diseases, as leukocyte and platelet activation is a key factor for the pathogenesis of both disease entities [176][177][178]. AAA pathogenesis is characterised by infiltration of the aortic wall by neutrophils, macrophages and lymphocytes [179]. Subsequently, secreted enzymes, proteases and cytokines lead to ECM degradation, e.g., of collagen and elastin fibres, and an increased rate of apoptosis of smooth muscle cells promoting destruction and dilation of the vessel wall [180].
Macrophages are thought to play a decisive role in AAA formation [178]. Accumulation of macrophages during aneurysm formation can be observed in all three layers of the vessel wall but is particularly pronounced in the adventitia and the intraluminal thrombus (ILT) [181][182]. While the role of different subsets of macrophages in the stages of AAA development is not yet fully elucidated, it is hypothesised that bone-marrow-derived macrophages extravasate into the aortic wall and contribute to inflammatory processes and early stages of AAA formation [178].
The recruitment of monocytes into the aortic wall has been shown to be largely dependent on monocyte chemotactic protein 1 (MCP-1) and IL-6 produced by aortic adventitial fibroblasts [183]. Tieu et al. have shown that recruited monocytes locally mature into macrophages, which in turn stimulate the activation of adjacent fibroblasts and the release of further pro-inflammatory cytokines, forming a vicious circle of macrophage–fibroblast activation [183][184].
The pathways involved in AAA monocyte recruitment are also thought to play a decisive role in atherogenesis [185]. The infusion of angiotensin 2 in an apolipoprotein-E-deficient mouse model prone to atherosclerosis was not only shown to increase the severity of atherosclerotic lesions, but also promote AAA formation [186]. Upon stimulation by angiotensin 2, aortic adventitial fibroblasts release MCP-1 and IL-6, which cause monocyte recruitment and differentiation, and cytokine release [183][184].
The chemokine receptor 2 (CCR-2) signal, which is induced by MCP-1, plays a central role in various inflammatory diseases, including cancer and CVD [187]. Tieu et al. have demonstrated that the knock-out of CCR-2 resulted in significantly reduced adventitial fibroblast proliferation in a murine model of AAA formation [183]. Conversely, the transfer of CCR-2 positive monocytes resulted in restored proliferation and restored AAA formation [183]. The MCP-1/CCR-2 axis is thought to be crucial to the initiation of atherogenesis by promoting monocyte accumulation in atherosclerotic lesions [183][184]. In addition, levels of MCP-1/CCR-2 expression are associated with plaque vulnerability [188].
The activation of TLR-2 and TLR-4 and their downstream signalling pathways, including, among others, MyD88, NF-ĸB, and mitogen-activated protein kinase, is also considered a relevant driver of both aneurysm formation and atherosclerosis [34][189][190]. As a consequence, inhibition of the TLR-4/MyD88/NF-ĸB pathway by statins conveys anti-inflammatory and anti-atherosclerotic properties [21].
Neutrophils are considered to be both regulators and effector cells of inflammation [191]. In the context of AAA formation, activated neutrophils contribute to chronic inflammation, mainly by releasing ROS, NETs, histones and neutrophil granule proteins [192][193][194].
The formation of an ILT is frequently observed in progressive AAA and a risk factor for AAA rupture [195][196]. An ILT with concomitant platelet activation contributes to inflammation, vessel remodelling and ECM degradation [197]. Platelets activated in the context of ILT formation secrete pro-inflammatory cytokines and chemokines, which in turn stimulate leukocyte recruitment, activation and, ultimately, AAA progression [196][197][198][199].
Klopf et al. have reviewed various parameters including neutrophil-derived markers of inflammation, e.g., gelatinase-associated lipocalin [200][201], neutrophil elastase [202], myeloperoxidase [203][204], MMP [205] and NETs [206], as potential biomarkers for prognosis in AAA [25]. While the exact mechanisms which lead to aortic wall inflammation and leukocyte recruitment are not yet fully elucidated, these findings illustrate the involved processes and may help establish a better understanding of both factors determining prognosis and potential new therapeutic targets in AAA [25].
Importantly, inflammatory processes evoked by different infections, e.g., Porphyromonas gingivalis, Epstein–Barr virus, cytomegalovirus or papillomavirus, are also being discussed as potential promoters of local inflammation and risk factors for aneurysm formation [207][208]. In fact, the presence of periodontal disease, mainly with Porphyromonas gingivalis [209], and the occurrence of periodontal bacteria in the bloodstream or in the vascular lesion is associated with AAA formation [210][211][212]. In patients with AAA, cytomegalovirus was detected about five times as often as in healthy volunteers and was associated with increased levels of pro-inflammatory TNF-α and higher rates of arterial hypertension and CAD [208][213].
In addition to inflammatory conditions, aneurysms may also occur on the basis of pathogenic gene variants [214]. The variants best established generally concern structural proteins, e.g., procollagen type III α1, transforming growth factor β and fibrillin 1, as seen in Marfan syndrome [214].

2.5. Vasculitis

Vasculitides are a group of rare diseases characterised by auto-immune inflammation of blood vessels of various sizes [215]. The introduction of targeted immuno-modulatory agents has improved prognosis and reduced mortality due to exacerbated vasculitis or infection drastically [216]. In patients with vasculitis, CVD is now the most common cause of death [217][218]. In addition, a chronic inflammatory state is independently associated with long-term mortality in patients with Raynaud’s phenomenon [219].
An acceleration of atherogenesis in patients with AAV has been previously demonstrated [220], and surrogate markers of endothelial dysfunction, e.g., endothelium-dependent dilation of the brachial artery or pulse-wave velocity, are increased in the context of AAV [221]. One study evaluated atherosclerotic plaque burden by means of ultrasound and found that, compared to a healthy control cohort, AAV patients had a significantly higher plaque burden in the abdominal aorta and the carotid and the femoral arteries [220]. It may be hypothesised that a continuous sub-clinical inflammatory state contributes to the acceleration of atherogenesis in these patients [222]. The shedding of the endothelial glycocalyx, endothelial dysfunction [223] with enhanced expression of leukocyte adhesion factors, and leukocyte-diapedesis into the vessel wall promote a pro-inflammatory and pro-coagulatory state [224][225]. Furthermore, risk factors commonly associated with atherosclerosis are more prevalent in patients with AAV [223][226].
However, it must be noted that solid evidence of accelerated atherosclerosis in vasculitides has thus far only been established for Kawasaki’s disease, Takayasu’s arteritis and, most prominently, AAV [222].
Despite advances in immuno-modulatory therapy and the application of novel biologic disease-modifying drugs, glucocorticoids are still frequently used for induction therapy and are associated with significant toxicity. Traditional risk factors for atherosclerosis, i.e., hypertension, hyperglycaemia and dyslipidaemia, are exacerbated in patients with frequent glucocorticoid intake [227]. Risk factor management for the prevention of cardiovascular events in these high-risk patients has been shown to be insufficient in many patients [14][228]. Even with advanced biologics, e.g., Janus kinase inhibitors, undesired cardiovascular effects may occur [229][230]. Evidence is conflicting and therapeutic benefits may depend on the specific disease entity [231][232].

2.6. The Influence of Inflammation on Angiogenesis, Arteriogenesis, and Collateralisation

While inflammation is generally regarded as deleterious in PAD, specific inflammatory pathways involved in atherogenesis also participate in tissue regeneration, angio- and arteriogenesis [233][234]. Angiogenesis is the process of the formation of new capillaries for improved tissue perfusion, while arteriogenesis describes the transformation of arterio-arteriolar anastomoses to fully functional collateral arteries [235]. Therefore, while angiogenesis primarily involves endothelial cells, arteriogenesis necessitates the proliferation, migration and transformation of vascular smooth muscle cells [235], the latter being promoted by inflammatory conditions [233].
Angiogenesis is induced by various cytokines, e.g., vascular growth factor (VEGF), fibroblast growth factor (FGF) and angiopoietin, and is regulated via HIF-1 [87][236]. The molecular pathways which lead to arteriogenesis additionally include a response to increased shear stress and blood flow in arterio-arteriolar anastomoses and require the recruitment of macrophages [87].
The recruitment of macrophages is regulated via intercellular adhesion molecule 1 (ICAM-1) and CCR-2 signalling and promoted by granulocyte-colony stimulating factor (G-CSF) and granulocyte macrophage-colony stimulating factor (GM-CSF) [87][237][238]. While the M1 macrophage population is largely responsible for tissue damage associated with inflammation, alternatively activated M2 macrophages modulate cell proliferation and transition and are involved in tissue regeneration by secretion of growth factors (VEGF, FGF), MMPs and NO [87][239]. However, pro-inflammatory M1 macrophages are especially considered crucial sources of VEGF-A in arteriogenesis [234]. In this context, inflammatory M1 macrophages upregulate the transcription of the pro-angiogenic VEGF-A isoform via autocrine IL-1β-mediated activation of NF-ĸB and signal transducer and activator of transcription 3 (STAT3) [234]. Conversely, in an IL-1β knock-out mouse model, VEGF-transcription depending on HIF-1 alone was markedly decreased in comparison to a wild-type IL-1β cohort, where VEGF transcription is promoted by both HIF-1 and IL-1β-dependent pathways [234][240][241] .

References

  1. Roth, G.A.; Mensah, G.A.; Johnson, C.O.; Addolorato, G.; Ammirati, E.; Baddour, L.M.; Barengo, N.C.; Beaton, A.; Benjamin, E.J.; Benziger, C.P.; et al. Global Burden of Cardiovascular Diseases and Risk Factors, 1990–2019: Update From the GBD 2019 Study. J. Am. Coll. Cardiol. 2020, 76, 2982–3021.
  2. Townsend, N.; Wilson, L.; Bhatnagar, P.; Wickramasinghe, K.; Rayner, M.; Nichols, M. Cardiovascular Disease in Europe: Epidemiological Update 2016. Eur. Heart J. 2016, 37, 3232–3245.
  3. Woolf, N. The Pathology of Atherosclerosis with Particular Reference to the Effects of Hyperlipidaemia. Eur. Heart J. 1987, 8 (Suppl. E), 3–14.
  4. Hedin, U.; Matic, L.P. Recent Advances in Therapeutic Targeting of Inflammation in Atherosclerosis. J. Vasc. Surg. 2019, 69, 944–951.
  5. Raggi, P.; Genest, J.; Giles, J.T.; Rayner, K.J.; Dwivedi, G.; Beanlands, R.S.; Gupta, M. Role of Inflammation in the Pathogenesis of Atherosclerosis and Therapeutic Interventions. Atherosclerosis 2018, 276, 98–108.
  6. Geovanini, G.R.; Libby, P. Atherosclerosis and Inflammation: Overview and Updates. Clin. Sci. 2018, 132, 1243–1252.
  7. Kong, P.; Cui, Z.Y.; Huang, X.F.; Zhang, D.D.; Guo, R.J.; Han, M. Inflammation and Atherosclerosis: Signaling Pathways and Therapeutic Intervention. Signal Transduct. Target. Ther. 2022, 7, 131.
  8. Soehnlein, O.; Libby, P. Targeting Inflammation in Atherosclerosis—From Experimental Insights to the Clinic. Nat. Rev. Drug Discov. 2021, 20, 589–610.
  9. Wadowski, P.P.; Panzer, B.; Józkowicz, A.; Kopp, C.W.; Gremmel, T.; Panzer, S.; Koppensteiner, R. Microvascular Thrombosis as a Critical Factor in Severe COVID-19. Int. J. Mol. Sci. 2023, 24, 2492.
  10. Steven, S.; Daiber, A.; Dopheide, J.F.; Münzel, T.; Espinola-Klein, C. Peripheral Artery Disease, Redox Signaling, Oxidative Stress—Basic and Clinical Aspects. Redox Biol. 2017, 12, 787–797.
  11. Yu, H.; Kalogeris, T.; Korthuis, R.J. Reactive Species-Induced Microvascular Dysfunction in Ischemia/Reperfusion. Free Radic. Biol. Med. 2019, 135, 182–197.
  12. Mason, J.C.; Libby, P. Cardiovascular Disease in Patients with Chronic Inflammation: Mechanisms Underlying Premature Cardiovascular Events in Rheumatologic Conditions. Eur. Heart J. 2015, 36, 482–489.
  13. Arida, A.; Protogerou, A.; Kitas, G.; Sfikakis, P. Systemic Inflammatory Response and Atherosclerosis: The Paradigm of Chronic Inflammatory Rheumatic Diseases. Int. J. Mol. Sci. 2018, 19, 1890.
  14. Poledniczek, M.H. Coronary Artery Disease in Granulomatosis with Polyangiitis: A Review. SN Compr. Clin. Med. 2022, 4, 75.
  15. Ridker, P.M.; Everett, B.M.; Thuren, T.; MacFadyen, J.G.; Chang, W.H.; Ballantyne, C.; Fonseca, F.; Nicolau, J.; Koenig, W.; Anker, S.D.; et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N. Engl. J. Med. 2017, 377, 1119–1131.
  16. Nidorf, S.M.; Fiolet, A.T.L.; Mosterd, A.; Eikelboom, J.W.; Schut, A.; Opstal, T.S.J.; The, S.H.K.; Xu, X.-F.; Ireland, M.A.; Lenderink, T.; et al. Colchicine in Patients with Chronic Coronary Disease. N. Engl. J. Med. 2020, 383, 1838–1847.
  17. Deftereos, S.G.; Beerkens, F.J.; Shah, B.; Giannopoulos, G.; Vrachatis, D.A.; Giotaki, S.G.; Siasos, G.; Nicolas, J.; Arnott, C.; Patel, S.; et al. Colchicine in Cardiovascular Disease: In-Depth Review. Circulation 2022, 145, 61–78.
  18. Visseren, F.L.J.; MacH, F.; Smulders, Y.M.; Carballo, D.; Koskinas, K.C.; Bäck, M.; Benetos, A.; Biffi, A.; Boavida, J.M.; Capodanno, D.; et al. 2021 ESC Guidelines on Cardiovascular Disease Prevention in Clinical Practice. Eur. Heart J. 2021, 42, 3227–3337.
  19. Darabseh, M.Z.; Maden-Wilkinson, T.M.; Welbourne, G.; Wüst, R.C.I.; Ahmed, N.; Aushah, H.; Selfe, J.; Morse, C.I.; Degens, H. Fourteen Days of Smoking Cessation Improves Muscle Fatigue Resistance and Reverses Markers of Systemic Inflammation. Sci. Rep. 2021, 11, 12286.
  20. McElroy, J.P.; Carmella, S.G.; Heskin, A.K.; Tang, M.K.; Murphy, S.E.; Reisinger, S.A.; Jensen, J.A.; Hatsukami, D.K.; Hecht, S.S.; Shields, P.G. Effects of Cessation of Cigarette Smoking on Eicosanoid Biomarkers of Inflammation and Oxidative Damage. PLoS ONE 2019, 14, e0218386.
  21. Koushki, K.; Shahbaz, S.K.; Mashayekhi, K.; Sadeghi, M.; Zayeri, Z.D.; Taba, M.Y.; Banach, M.; Al-Rasadi, K.; Johnston, T.P.; Sahebkar, A. Anti-Inflammatory Action of Statins in Cardiovascular Disease: The Role of Inflammasome and Toll-Like Receptor Pathways. Clin. Rev. Allergy Immunol. 2021, 60, 175–199.
  22. Aboyans, V.; Ricco, J.B.; Bartelink, M.L.E.L.; Björck, M.; Brodmann, M.; Cohnert, T.; Collet, J.P.; Czerny, M.; De Carlo, M.; Debus, S.; et al. 2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in Collaboration with the European Society for Vascular Surgery (ESVS). Eur. Heart J. 2018, 39, 763–816.
  23. Yuan, Z.; Lu, Y.; Wei, J.; Wu, J.; Yang, J.; Cai, Z. Abdominal Aortic Aneurysm: Roles of Inflammatory Cells. Front. Immunol. 2020, 11, 609161.
  24. Tilson, M.D. Decline of the Atherogenic Theory of the Etiology of the Abdominal Aortic Aneurysm and Rise of the Autoimmune Hypothesis. J. Vasc. Surg. 2016, 64, 1523–1525.
  25. Klopf, J.; Brostjan, C.; Neumayer, C.; Eilenberg, W. Neutrophils as Regulators and Biomarkers of Cardiovascular Inflammation in the Context of Abdominal Aortic Aneurysms. Biomedicines 2021, 9, 1236.
  26. Reitsma, S.; Oude Egbrink, M.G.; Heijnen, V.V.T.; Megens, R.T.A.; Engels, W.; Vink, H.; Slaaf, D.W.; van Zandvoort, M.A.M.J. Endothelial Glycocalyx Thickness and Platelet-Vessel Wall Interactions during Atherogenesis. Thromb. Haemost. 2011, 106, 939–946.
  27. Reitsma, S.; Slaaf, D.W.; Vink, H.; Van Zandvoort, M.A.M.J.; Oude Egbrink, M.G.A. The Endothelial Glycocalyx: Composition, Functions, and Visualization. Pflug. Arch. 2007, 454, 345–359.
  28. Lipowsky, H.H. Protease Activity and the Role of the Endothelial Glycocalyx in Inflammation. Drug Discov. Today Dis. Models 2011, 8, 57.
  29. van der Poll, T.; Parker, R.I. Platelet Activation and Endothelial Cell Dysfunction. Crit. Care Clin. 2020, 36, 233–253.
  30. Dull, R.O.; Hahn, R.G. The Glycocalyx as a Permeability Barrier: Basic Science and Clinical Evidence. Crit. Care 2022, 26, 273.
  31. Fels, B.; Kusche-Vihrog, K. It Takes More than Two to Tango: Mechanosignaling of the Endothelial Surface. Pflug. Arch. 2020, 472, 419–433.
  32. Mitra, R.; O’Neil, G.L.; Harding, I.C.; Cheng, M.J.; Mensah, S.A.; Ebong, E.E. Glycocalyx in Atherosclerosis-Relevant Endothelium Function and as a Therapeutic Target. Curr. Atheroscler. Rep. 2017, 19, 63.
  33. Qu, J.; Cheng, Y.; Wu, W.; Yuan, L.; Liu, X. Glycocalyx Impairment in Vascular Disease: Focus on Inflammation. Front. Cell Dev. Biol. 2021, 9, 730621.
  34. Panzer, B.; Kopp, C.W.; Neumayer, C.; Koppensteiner, R.; Jozkowicz, A.; Poledniczek, M.; Gremmel, T.; Jilma, B.; Wadowski, P.P. Toll-like Receptors as Pro-Thrombotic Drivers in Viral Infections: A Narrative Review. Cells 2023, 12, 1865.
  35. Maschalidi, S.; Ravichandran, K.S. Phagocytosis: Sweet Repulsions via the Glycocalyx. Curr. Biol. 2021, 31, R20–R22.
  36. Imbert, P.R.C.; Saric, A.; Pedram, K.; Bertozzi, C.R.; Grinstein, S.; Freeman, S.A. An Acquired and Endogenous Glycocalyx Forms a Bidirectional “Don’t Eat” and “Don’t Eat Me” Barrier to Phagocytosis. Curr. Biol. 2021, 31, 77–89.e5.
  37. Marki, A.; Esko, J.D.; Pries, A.R.; Ley, K. Role of the Endothelial Surface Layer in Neutrophil Recruitment. J. Leukoc. Biol. 2015, 98, 503–515.
  38. Möckl, L. The Emerging Role of the Mammalian Glycocalyx in Functional Membrane Organization and Immune System Regulation. Front. Cell Dev. Biol. 2020, 8, 253.
  39. Doster, R.S.; Rogers, L.M.; Gaddy, J.A.; Aronoff, D.M. Macrophage Extracellular Traps: A Scoping Review. J. Innate Immun. 2018, 10, 3–13.
  40. Je, S.; Quan, H.; Yoon, Y.; Na, Y.; Kim, B.J.; Seok, S.H. Mycobacterium Massiliense Induces Macrophage Extracellular Traps with Facilitating Bacterial Growth. PLoS ONE 2016, 11, e0155685.
  41. Fu, G.; Deng, M.; Neal, M.D.; Billiar, T.R.; Scott, M.J. Platelet-Monocyte Aggregates: Understanding Mechanisms and Functions in Sepsis. Shock 2021, 55, 156–166.
  42. Kaiser, R.; Escaig, R.; Erber, J.; Nicolai, L. Neutrophil-Platelet Interactions as Novel Treatment Targets in Cardiovascular Disease. Front. Cardiovasc. Med. 2022, 8, 824112.
  43. Qi, H.; Yang, S.; Zhang, L. Neutrophil Extracellular Traps and Endothelial Dysfunction in Atherosclerosis and Thrombosis. Front. Immunol. 2017, 8, 928.
  44. Banerjee, S.; Mwangi, J.G.; Stanley, T.K.; Mitra, R.; Ebong, E.E. Regeneration and Assessment of the Endothelial Glycocalyx to Address Cardiovascular Disease. Ind. Eng. Chem. Res. 2021, 60, 17328–17347.
  45. Steven, S.; Frenis, K.; Oelze, M.; Kalinovic, S.; Kuntic, M.; Jimenez, M.T.B.; Vujacic-Mirski, K.; Helmstädter, J.; Kröller-Schön, S.; Münzel, T.; et al. Vascular Inflammation and Oxidative Stress: Major Triggers for Cardiovascular Disease. Oxid. Med. Cell Longev. 2019, 2019, 7092151.
  46. Ofosu, F.A.; Dewar, L.; Craven, S.J.; Song, Y.; Cedrone, A.; Freedman, J.; Fenton, J.W. Coordinate Activation of Human Platelet Protease-Activated Receptor-1 and -4 in Response to Subnanomolar Alpha-Thrombin. J. Biol. Chem. 2008, 283, 26886–26893.
  47. Wadowski, P.P.; Pultar, J.; Weikert, C.; Eichelberger, B.; Panzer, B.; Huber, K.; Lang, I.M.; Koppensteiner, R.; Panzer, S.; Gremmel, T. Protease-Activated Receptor-Mediated Platelet Aggregation in Acute Coronary Syndrome Patients on Potent P2Y12 Inhibitors. Res. Pract. Thromb. Haemost. 2019, 3, 383–390.
  48. Adam, F.; Guillin, M.C.; Jandrot-Perrus, M. Glycoprotein Ib-Mediated Platelet Activation. A Signalling Pathway Triggered by Thrombin. Eur. J. Biochem. 2003, 270, 2959–2970.
  49. Hally, K.; Fauteux-Daniel, S.; Hamzeh-Cognasse, H.; Larsen, P.; Cognasse, F. Revisiting Platelets and Toll-Like Receptors (TLRs): At the Interface of Vascular Immunity and Thrombosis. Int. J. Mol. Sci. 2020, 21, 6150.
  50. Niklaus, M.; Klingler, P.; Weber, K.; Koessler, A.; Kuhn, S.; Boeck, M.; Kobsar, A.; Koessler, J. Platelet Toll-Like-Receptor-2 and -4 Mediate Different Immune-Related Responses to Bacterial Ligands. TH Open 2022, 6, e156–e167.
  51. Salvador, B.; Arranz, A.; Francisco, S.; Córdoba, L.; Punzón, C.; Llamas, M.Á.; Fresno, M. Modulation of Endothelial Function by Toll like Receptors. Pharmacol. Res. 2016, 108, 46–56.
  52. O’Neill, L.A.J. DisSARMing Toll-like Receptor Signaling. Nat. Immunol. 2006, 7, 1023–1025.
  53. Akira, S.; Takeda, K. Toll-like Receptor Signalling. Nat. Rev. Immunol. 2004, 4, 499–511.
  54. Schilling, D.; Thomas, K.; Nixdorff, K.; Vogel, S.N.; Fenton, M.J. Toll-Like Receptor 4 and Toll-IL-1 Receptor Domain-Containing Adapter Protein (TIRAP)/Myeloid Differentiation Protein 88 Adapter-Like (Mal) Contribute to Maximal IL-6 Expression in Macrophages. J. Immunol. 2002, 169, 5874–5880.
  55. Carty, M.; Goodbody, R.; Schröder, M.; Stack, J.; Moynagh, P.N.; Bowie, A.G. The Human Adaptor SARM Negatively Regulates Adaptor Protein TRIF–Dependent Toll-like Receptor Signaling. Nat. Immunol. 2006, 7, 1074–1081.
  56. El-Zayat, S.R.; Sibaii, H.; Mannaa, F.A. Toll-like Receptors Activation, Signaling, and Targeting: An Overview. Bull. Natl. Res. Cent. 2019, 43, 187.
  57. Liu, T.; Zhang, L.; Joo, D.; Sun, S.C. NF-ΚB Signaling in Inflammation. Signal Transduct. Target. Ther. 2017, 2, 17023.
  58. Rubio, D.; Xu, R.H.; Remakus, S.; Krouse, T.E.; Truckenmiller, M.E.; Thapa, R.J.; Balachandran, S.; Alcamí, A.; Norbury, C.C.; Sigal, L.J. Crosstalk between the Type 1 Interferon and Nuclear Factor Kappa B Pathways Confers Resistance to a Lethal Virus Infection. Cell Host Microbe 2013, 13, 701–710.
  59. Ernst, O.; Vayttaden, S.J.; Fraser, I.D.C. Measurement of NF-ΚB Activation in TLR-Activated Macrophages. Methods Mol. Biol. 2018, 1714, 67–78.
  60. Qiao, Y.; Wang, P.; Qi, J.; Zhang, L.; Gao, C. TLR-Induced NF-ΚB Activation Regulates NLRP3 Expression in Murine Macrophages. FEBS Lett. 2012, 586, 1022–1026.
  61. Grebe, A.; Hoss, F.; Latz, E. NLRP3 Inflammasome and the IL-1 Pathway in Atherosclerosis. Circ. Res. 2018, 122, 1722–1740.
  62. Bartoli-Leonard, F.; Zimmer, J.; Sonawane, A.R.; Perez, K.; Turner, M.E.; Kuraoka, S.; Pham, T.; Li, F.; Aikawa, M.; Singh, S.; et al. NLRP3 Inflammasome Activation in Peripheral Arterial Disease. J. Am. Heart Assoc. 2023, 12, e026945.
  63. Bai, B.; Yang, Y.; Wang, Q.; Li, M.; Tian, C.; Liu, Y.; Aung, L.H.H.; Li, P.; Yu, T.; Chu, X.M. NLRP3 Inflammasome in Endothelial Dysfunction. Cell Death Dis. 2020, 11, 776.
  64. Lee, Y.; Reilly, B.; Tan, C.; Wang, P.; Aziz, M. Extracellular CIRP Induces Macrophage Extracellular Trap Formation Via Gasdermin D Activation. Front. Immunol. 2021, 12, 780210.
  65. Hally, K.E.; Bird, G.K.; la Flamme, A.C.; Harding, S.A.; Larsen, P.D. Platelets Modulate Multiple Markers of Neutrophil Function in Response to in Vitro Toll-like Receptor Stimulation. PLoS ONE 2019, 14, e0223444.
  66. Clark, S.R.; Ma, A.C.; Tavener, S.A.; McDonald, B.; Goodarzi, Z.; Kelly, M.M.; Patel, K.D.; Chakrabarti, S.; McAvoy, E.; Sinclair, G.D.; et al. Platelet TLR4 Activates Neutrophil Extracellular Traps to Ensnare Bacteria in Septic Blood. Nat. Med. 2007, 13, 463–469.
  67. Zhang, D.; Chen, G.; Manwani, D.; Mortha, A.; Xu, C.; Faith, J.J.; Burk, R.D.; Kunisaki, Y.; Jang, J.E.; Scheiermann, C.; et al. Neutrophil Ageing Is Regulated by the Microbiome. Nature 2015, 525, 528–532.
  68. Katakami, N. Mechanism of Development of Atherosclerosis and Cardiovascular Disease in Diabetes Mellitus. J. Atheroscler. Thromb. 2018, 25, 27–39.
  69. Mulivor, A.W.; Lipowsky, H.H. Inflammation- and Ischemia-Induced Shedding of Venular Glycocalyx. Am. J. Physiol. Heart Circ. Physiol. 2004, 286, H1672–H1680.
  70. Dogné, S.; Flamion, B.; Caron, N. Endothelial Glycocalyx as a Shield Against Diabetic Vascular Complications: Involvement of Hyaluronan and Hyaluronidases. Arter. Thromb. Vasc. Biol. 2018, 38, 1427.
  71. Lee, D.H.; Dane, M.J.C.; Van Den Berg, B.M.; Boels, M.G.S.; Van Teeffelen, J.W.; De Mutsert, R.; Den Heijer, M.; Rosendaal, F.R.; Van Der Vlag, J.; Van Zonneveld, A.J.; et al. Deeper Penetration of Erythrocytes into the Endothelial Glycocalyx Is Associated with Impaired Microvascular Perfusion. PLoS ONE 2014, 9, e96477.
  72. Rabelink, T.J.; De Zeeuw, D. The Glycocalyx--Linking Albuminuria with Renal and Cardiovascular Disease. Nat. Rev. Nephrol. 2015, 11, 667–676.
  73. Liew, H.; Roberts, M.A.; MacGinley, R.; McMahon, L.P. Endothelial Glycocalyx in Health and Kidney Disease: Rising Star or False Dawn? Nephrology 2017, 22, 940–946.
  74. Wadowski, P.P.; Kautzky-Willer, A.; Gremmel, T.; Koppensteiner, R.; Wolf, P.; Ertl, S.; Weikert, C.; Schörgenhofer, C.; Jilma, B. Sublingual Microvasculature in Diabetic Patients. Microvasc. Res. 2020, 129, 103971.
  75. Hirano, T. Pathophysiology of Diabetic Dyslipidemia. J. Atheroscler. Thromb. 2018, 25, 771–782.
  76. Hagensen, M.K.; Mortensen, M.B.; Kjolby, M.; Palmfeldt, J.; Bentzon, J.F.; Gregersen, S. Increased Retention of LDL from Type 1 Diabetic Patients in Atherosclerosis-Prone Areas of the Murine Arterial Wall. Atherosclerosis 2019, 286, 156–162.
  77. Singh, S.; Siva, B.V.; Ravichandiran, V. Advanced Glycation End Products: Key Player of the Pathogenesis of Atherosclerosis. Glycoconj. J. 2022, 39, 547–563.
  78. Palmieri, E.M.; Gonzalez-Cotto, M.; Baseler, W.A.; Davies, L.C.; Ghesquière, B.; Maio, N.; Rice, C.M.; Rouault, T.A.; Cassel, T.; Higashi, R.M.; et al. Nitric Oxide Orchestrates Metabolic Rewiring in M1 Macrophages by Targeting Aconitase 2 and Pyruvate Dehydrogenase. Nat. Commun. 2020, 11, 698.
  79. Vujic, A.; Koo, A.N.M.; Prag, H.A.; Krieg, T. Mitochondrial Redox and TCA Cycle Metabolite Signaling in the Heart. Free Radic. Biol. Med. 2021, 166, 287–296.
  80. Tannahill, G.M.; Curtis, A.M.; Adamik, J.; Palsson-Mcdermott, E.M.; McGettrick, A.F.; Goel, G.; Frezza, C.; Bernard, N.J.; Kelly, B.; Foley, N.H.; et al. Succinate Is an Inflammatory Signal That Induces IL-1β through HIF-1α. Nature 2013, 496, 238–242.
  81. O’Neill, L.A.J.; Pearce, E.J. Immunometabolism Governs Dendritic Cell and Macrophage Function. J. Exp. Med. 2016, 213, 15–23.
  82. Chouchani, E.T.; Pell, V.R.; Gaude, E.; Aksentijević, D.; Sundier, S.Y.; Robb, E.L.; Logan, A.; Nadtochiy, S.M.; Ord, E.N.J.; Smith, A.C.; et al. Ischaemic Accumulation of Succinate Controls Reperfusion Injury through Mitochondrial ROS. Nature 2014, 515, 431–435.
  83. Lee, W.J.; Tateya, S.; Cheng, A.M.; Rizzo-Deleon, N.; Wang, N.F.; Handa, P.; Wilson, C.L.; Clowes, A.W.; Sweet, I.R.; Bomsztyk, K.; et al. M2 Macrophage Polarization Mediates Anti-Inflammatory Effects of Endothelial Nitric Oxide Signaling. Diabetes 2015, 64, 2836–2846.
  84. Steiner, S.; Schaller, G.; Puttinger, H.; Födinger, M.; Kopp, C.W.; Seidinger, D.; Grisar, J.; Hörl, W.H.; Minar, E.; Vychytil, A.; et al. History of Cardiovascular Disease Is Associated with Endothelial Progenitor Cells in Peritoneal Dialysis Patients. Am. J. Kidney Dis. 2005, 46, 520–528.
  85. Ambasta, R.K.; Kohli, H.; Kumar, P. Multiple Therapeutic Effect of Endothelial Progenitor Cell Regulated by Drugs in Diabetes and Diabetes Related Disorder. J. Transl. Med. 2017, 15, 185.
  86. Sandri, M.; Beck, E.B.; Adams, V.; Gielen, S.; Lenk, K.; Höllriegel, R.; Mangner, N.; Linke, A.; Erbs, S.; Möbius-Winkler, S.; et al. Maximal Exercise, Limb Ischemia, and Endothelial Progenitor Cells. Eur. J. Cardiovasc. Prev. Rehabil. 2011, 18, 55–64.
  87. Cooke, J.P.; Meng, S. Vascular Regeneration in Peripheral Artery Disease. Arter. Thromb. Vasc. Biol. 2020, 40, 1627–1634.
  88. Yamaguchi, J.I.; Kusano, K.F.; Masuo, O.; Kawamoto, A.; Silver, M.; Murasawa, S.; Bosch-Marce, M.; Masuda, H.; Losordo, D.W.; Isner, J.M.; et al. Stromal Cell-Derived Factor-1 Effects on Ex Vivo Expanded Endothelial Progenitor Cell Recruitment for Ischemic Neovascularization. Circulation 2003, 107, 1322–1328.
  89. He, J.; Xiao, Z.; Chen, X.; Chen, M.; Fang, L.; Yang, M.; Lv, Q.; Li, Y.; Li, G.; Hu, J.; et al. The Expression of Functional Toll-like Receptor 4 Is Associated with Proliferation and Maintenance of Stem Cell Phenotype in Endothelial Progenitor Cells (EPCs). J. Cell Biochem. 2010, 111, 179–186.
  90. Matsumoto, Y.; Adams, V.; Walther, C.; Kleinecke, C.; Brugger, P.; Linke, A.; Walther, T.; Mohr, F.W.; Schuler, G. Reduced Number and Function of Endothelial Progenitor Cells in Patients with Aortic Valve Stenosis: A Novel Concept for Valvular Endothelial Cell Repair. Eur. Heart J. 2009, 30, 346–355.
  91. Stoiber, W.; Obermayer, A.; Steinbacher, P.; Krautgartner, W.D. The Role of Reactive Oxygen Species (ROS) in the Formation of Extracellular Traps (ETs) in Humans. Biomolecules 2015, 5, 702–723.
  92. Ali, M.A.M.; Spinler, S.A. COVID-19 and Thrombosis: From Bench to Bedside. Trends Cardiovasc. Med. 2021, 31, 143–160.
  93. Wadowski, P.P.; Jilma, B.; Kopp, C.W.; Ertl, S.; Gremmel, T.; Koppensteiner, R. Glycocalyx as Possible Limiting Factor in COVID-19. Front. Immunol. 2021, 12, 607306.
  94. Borrmann, M.; Brandes, F.; Kirchner, B.; Klein, M.; Billaud, J.N.; Reithmair, M.; Rehm, M.; Schelling, G.; Pfaffl, M.W.; Meidert, A.S. Extensive Blood Transcriptome Analysis Reveals Cellular Signaling Networks Activated by Circulating Glycocalyx Components Reflecting Vascular Injury in COVID-19. Front. Immunol. 2023, 14, 1129766.
  95. Varga, Z.; Flammer, A.J.; Steiger, P.; Haberecker, M.; Andermatt, R.; Zinkernagel, A.S.; Mehra, M.R.; Schuepbach, R.A.; Ruschitzka, F.; Moch, H. Endothelial Cell Infection and Endotheliitis in COVID-19. Lancet 2020, 395, 1417–1418.
  96. Xu, S.W.; Ilyas, I.; Weng, J.P. Endothelial Dysfunction in COVID-19: An Overview of Evidence, Biomarkers, Mechanisms and Potential Therapies. Acta Pharmacol. Sin. 2023, 44, 695–709.
  97. Ratajczak, J.; Wysoczynski, M.; Hayek, F.; Janowska-Wieczorek, A.; Ratajczak, M.Z. Membrane-Derived Microvesicles: Important and Underappreciated Mediators of Cell-to-Cell Communication. Leukemia 2006, 20, 1487–1495.
  98. Chen, Y.T.; Yuan, H.X.; Ou, Z.J.; Ou, J.S. Microparticles (Exosomes) and Atherosclerosis. Curr. Atheroscler. Rep. 2020, 22, 23.
  99. Loyer, X.; Vion, A.C.; Tedgui, A.; Boulanger, C.M. Microvesicles as Cell-Cell Messengers in Cardiovascular Diseases. Circ. Res. 2014, 114, 345–353.
  100. Février, B.; Raposo, G. Exosomes: Endosomal-Derived Vesicles Shipping Extracellular Messages. Curr. Opin. Cell Biol. 2004, 16, 415–421.
  101. Kalluri, R.; LeBleu, V.S. The Biology, Function, and Biomedical Applications of Exosomes. Science 2020, 367, eaau6977.
  102. Hosseinkhani, B.; Kuypers, S.; van den Akker, N.M.S.; Molin, D.G.M.; Michiels, L. Extracellular Vesicles Work as a Functional Inflammatory Mediator Between Vascular Endothelial Cells and Immune Cells. Front. Immunol. 2018, 9, 1789.
  103. Wendt, S.; Goetzenich, A.; Goettsch, C.; Stoppe, C.; Bleilevens, C.; Kraemer, S.; Benstoem, C. Evaluation of the Cardioprotective Potential of Extracellular Vesicles—A Systematic Review and Meta-Analysis. Sci. Rep. 2018, 8, 15702.
  104. George, M.; Ganesh, M.R.; Sridhar, A.; Jena, A.; Rajaram, M.; Shanmugam, E.; Dhandapani, V.E. Evaluation of Endothelial and Platelet Derived Microparticles in Patients with Acute Coronary Syndrome. J. Clin. Diagn. Res. 2015, 9, OC09–OC13.
  105. Tousoulis, D.; Kampoli, A.-M.; Tentolouris Nikolaos Papageorgiou, C.; Stefanadis, C. The Role of Nitric Oxide on Endothelial Function. Curr. Vasc. Pharmacol. 2012, 10, 4–18.
  106. Huang, P.L.; Huang, Z.; Mashimo, H.; Bloch, K.D.; Moskowitz, M.A.; Bevan, J.A.; Fishman, M.C. Hypertension in Mice Lacking the Gene for Endothelial Nitric Oxide Synthase. Nature 1995, 377, 239–242.
  107. Gimbrone, M.A.; García-Cardeña, G. Endothelial Cell Dysfunction and the Pathobiology of Atherosclerosis. Circ. Res. 2016, 118, 620–636.
  108. Stary, H.C. Natural History and Histological Classification of Atherosclerotic Lesions: An Update. Arter. Thromb. Vasc. Biol. 2000, 20, 1177–1178.
  109. Mittal, M.; Siddiqui, M.R.; Tran, K.; Reddy, S.P.; Malik, A.B. Reactive Oxygen Species in Inflammation and Tissue Injury. Antioxid. Redox Signal 2014, 20, 1126–1167.
  110. Incalza, M.A.; D’Oria, R.; Natalicchio, A.; Perrini, S.; Laviola, L.; Giorgino, F. Oxidative Stress and Reactive Oxygen Species in Endothelial Dysfunction Associated with Cardiovascular and Metabolic Diseases. Vasc. Pharmacol. 2018, 100, 1–19.
  111. Zhou, R.; Yazdi, A.S.; Menu, P.; Tschopp, J. A Role for Mitochondria in NLRP3 Inflammasome Activation. Nature 2011, 469, 221–226.
  112. Bulua, A.C.; Simon, A.; Maddipati, R.; Pelletier, M.; Park, H.; Kim, K.Y.; Sack, M.N.; Kastner, D.L.; Siegel, R.M. Mitochondrial Reactive Oxygen Species Promote Production of Proinflammatory Cytokines and Are Elevated in TNFR1-Associated Periodic Syndrome (TRAPS). J. Exp. Med. 2011, 208, 519–533.
  113. Ryan, K.A.; Smith, M.F.; Sanders, M.K.; Ernst, P.B. Reactive Oxygen and Nitrogen Species Differentially Regulate Toll-Like Receptor 4-Mediated Activation of NF-ΚB and Interleukin-8 Expression. Infect. Immun. 2004, 72, 2123.
  114. Zhang, J.; Wang, X.; Vikash, V.; Ye, Q.; Wu, D.; Liu, Y.; Dong, W. ROS and ROS-Mediated Cellular Signaling. Oxid. Med. Cell Longev. 2016, 2016, 4350965.
  115. Qiu, Q.; Yang, Z.; Cao, F.; Yang, C.; Hardy, P.; Yan, X.; Yang, S.; Xiong, W. Activation of NLRP3 Inflammasome by Lymphocytic Microparticles via TLR4 Pathway Contributes to Airway Inflammation. Exp. Cell Res. 2020, 386, 111737.
  116. Jerez-Dolz, D.; Torramade-Moix, S.; Palomo, M.; Moreno-Castaño, A.; Lopez-Vilchez, I.; Hernandez, R.; Badimon, J.J.; Zafar, M.U.; Diaz-Ricart, M.; Escolar, G. Internalization of Microparticles by Platelets Is Partially Mediated by Toll-like Receptor 4 and Enhances Platelet Thrombogenicity. Atherosclerosis 2020, 294, 17–24.
  117. Zhang, W.; Liu, R.; Chen, Y.; Wang, M.; Du, J. Crosstalk between Oxidative Stress and Exosomes. Oxid. Med. Cell Longev. 2022, 2022, 3553617.
  118. Jansen, F.; Yang, X.; Franklin, B.S.; Hoelscher, M.; Schmitz, T.; Bedorf, J.; Nickenig, G.; Werner, N. High Glucose Condition Increases NADPH Oxidase Activity in Endothelial Microparticles That Promote Vascular Inflammation. Cardiovasc. Res. 2013, 98, 94–106.
  119. Mause, S.F.; Weber, C. Microparticles: Protagonists of a Novel Communication Network for Intercellular Information Exchange. Circ. Res. 2010, 107, 1047–1057.
  120. Ci, H.B.; Ou, Z.J.; Chang, F.J.; Liu, D.H.; He, G.W.; Xu, Z.; Yuan, H.Y.; Wang, Z.P.; Zhang, X.; Ou, J.S. Endothelial Microparticles Increase in Mitral Valve Disease and Impair Mitral Valve Endothelial Function. Am. J. Physiol. Endocrinol. Metab. 2013, 304, E695–E702.
  121. Densmore, J.C.; Signorino, P.R.; Ou, J.; Hatoum, O.A.; Rowe, J.J.; Shi, Y.; Kaul, S.; Jones, D.W.; Sabina, R.E.; Pritchard, K.A.; et al. Endothelium-Derived Microparticles Induce Endothelial Dysfunction and Acute Lung Injury. Shock 2006, 26, 464–471.
  122. Lukasik, M.; Rozalski, M.; Luzak, B.; Michalak, M.; Ambrosius, W.; Watala, C.; Kozubski, W. Enhanced Platelet-Derived Microparticle Formation Is Associated with Carotid Atherosclerosis in Convalescent Stroke Patients. Platelets 2013, 24, 63–70.
  123. Lin, Z.B.; Ci, H.B.; Li, Y.; Cheng, T.P.; Liu, D.H.; Wang, Y.S.; Xu, J.; Yuan, H.X.; Li, H.M.; Chen, J.; et al. Endothelial Microparticles Are Increased in Congenital Heart Diseases and Contribute to Endothelial Dysfunction. J. Transl. Med. 2017, 15, 4.
  124. Xie, Z.; Wang, X.; Liu, X.; Du, H.; Sun, C.; Shao, X.; Tian, J.; Gu, X.; Wang, H.; Tian, J.; et al. Adipose-Derived Exosomes Exert Proatherogenic Effects by Regulating Macrophage Foam Cell Formation and Polarization. J. Am. Heart Assoc. 2018, 7, e007442.
  125. Blaser, M.C.; Aikawa, E. Differential MiRNA Loading Underpins Dual Harmful and Protective Roles for Extracellular Vesicles in Atherogenesis. Circ. Res. 2019, 124, 467–469.
  126. Li, C.; Li, S.; Zhang, F.; Wu, M.; Liang, H.; Song, J.; Lee, C.; Chen, H. Endothelial Microparticles-Mediated Transfer of MicroRNA-19b Promotes Atherosclerosis via Activating Perivascular Adipose Tissue Inflammation in ApoE-/- Mice. Biochem. Biophys. Res. Commun. 2018, 495, 1922–1929.
  127. Ceolotto, G.; Giannella, A.; Albiero, M.; Kuppusamy, M.; Radu, C.; Simioni, P.; Garlaschelli, K.; Baragetti, A.; Catapano, A.L.; Iori, E.; et al. MiR-30c-5p Regulates Macrophage-Mediated Inflammation and pro-Atherosclerosis Pathways. Cardiovasc. Res. 2017, 113, 1627–1638.
  128. Pereira-Da-silva, T.; Napoleão, P.; Costa, M.C.; Gabriel, A.F.; Selas, M.; Silva, F.; Enguita, F.J.; Ferreira, R.C.; Carmo, M.M. Cigarette Smoking, MiR-27b Downregulation, and Peripheral Artery Disease: Insights into the Mechanisms of Smoking Toxicity. J. Clin. Med. 2021, 10, 890.
  129. Badacz, R.; Kleczyński, P.; Legutko, J.; Żmudka, K.; Gacoń, J.; Przewłocki, T.; Kabłak-Ziembicka, A. Expression of MiR-1-3p, MiR-16-5p and MiR-122-5p as Possible Risk Factors of Secondary Cardiovascular Events. Biomedicines 2021, 9, 1055.
  130. Wronska, A.; Kurkowska-Jastrzebska, I.; Santulli, G. Application of MicroRNAs in Diagnosis and Treatment of Cardiovascular Disease. Acta Physiol. 2015, 213, 60–83.
  131. Wang, M.; Zhang, W.; Zhang, L.; Wang, L.; Li, J.; Shu, C.; Li, X. Roles of MicroRNAs in Peripheral Artery In-Stent Restenosis after Endovascular Treatment. Biomed. Res. Int. 2021, 2021, 9935671.
  132. Arroyo, J.D.; Chevillet, J.R.; Kroh, E.M.; Ruf, I.K.; Pritchard, C.C.; Gibson, D.F.; Mitchell, P.S.; Bennett, C.F.; Pogosova-Agadjanyan, E.L.; Stirewalt, D.L.; et al. Argonaute2 Complexes Carry a Population of Circulating MicroRNAs Independent of Vesicles in Human Plasma. Proc. Natl. Acad. Sci. USA 2011, 108, 5003–5008.
  133. Vickers, K.C.; Palmisano, B.T.; Shoucri, B.M.; Shamburek, R.D.; Remaley, A.T. MicroRNAs Are Transported in Plasma and Delivered to Recipient Cells by High-Density Lipoproteins. Nat. Cell Biol. 2011, 13, 423–435.
  134. Stojkovic, S.; Jurisic, M.; Kopp, C.W.; Koppensteiner, R.; Huber, K.; Wojta, J.; Gremmel, T. Circulating MicroRNAs Identify Patients at Increased Risk of In-Stent Restenosis after Peripheral Angioplasty with Stent Implantation. Atherosclerosis 2018, 269, 197–203.
  135. Badacz, R.; Przewłocki, T.; Legutko, J.; Żmudka, K.; Kabłak-Ziembicka, A. MicroRNAs Associated with Carotid Plaque Development and Vulnerability: The Clinician’s Perspective. Int. J. Mol. Sci. 2022, 23, 15645.
  136. Stojkovic, S.; Wadowski, P.P.; Haider, P.; Weikert, C.; Pultar, J.; Lee, S.; Eichelberger, B.; Hengstenberg, C.; Wojta, J.; Panzer, S.; et al. Circulating MicroRNAs and Monocyte-Platelet Aggregate Formation in Acute Coronary Syndrome. Thromb. Haemost. 2021, 121, 913–922.
  137. Finn, N.A.; Eapen, D.; Manocha, P.; Al Kassem, H.; Lassegue, B.; Ghasemzadeh, N.; Quyyumi, A.; Searles, C.D. Coronary Heart Disease Alters Intercellular Communication by Modifying Microparticle-Mediated MicroRNA Transport. FEBS Lett. 2013, 587, 3456–3463.
  138. Alexandru, N.; Andrei, E.; Niculescu, L.; Dragan, E.; Ristoiu, V.; Georgescu, A. Microparticles of Healthy Origins Improve Endothelial Progenitor Cell Dysfunction via MicroRNA Transfer in an Atherosclerotic Hamster Model. Acta Physiol. 2017, 221, 230–249.
  139. Brinkmann, V.; Reichard, U.; Goosmann, C.; Fauler, B.; Uhlemann, Y.; Weiss, D.S.; Weinrauch, Y.; Zychlinsky, A. Neutrophil Extracellular Traps Kill Bacteria. Science 2004, 303, 1532–1535.
  140. Rada, B. Neutrophil Extracellular Traps. Methods Mol. Biol. 2019, 1982, 517–528.
  141. Schönrich, G.; Raftery, M.J. Neutrophil Extracellular Traps Go Viral. Front. Immunol. 2016, 7, 366.
  142. Arneth, B.; Arneth, R. Neutrophil Extracellular Traps (NETs) and Vasculitis. Int. J. Med. Sci. 2021, 18, 1532–1540.
  143. Nappi, F.; Bellomo, F.; Avtaar Singh, S.S. Worsening Thrombotic Complication of Atherosclerotic Plaques Due to Neutrophils Extracellular Traps: A Systematic Review. Biomedicines 2023, 11, 113.
  144. Gupta, A.K.; Joshi, M.B.; Philippova, M.; Erne, P.; Hasler, P.; Hahn, S.; Resink, T.J. Activated Endothelial Cells Induce Neutrophil Extracellular Traps and Are Susceptible to NETosis-Mediated Cell Death. FEBS Lett. 2010, 584, 3193–3197.
  145. Saffarzadeh, M.; Juenemann, C.; Queisser, M.A.; Lochnit, G.; Barreto, G.; Galuska, S.P.; Lohmeyer, J.; Preissner, K.T. Neutrophil Extracellular Traps Directly Induce Epithelial and Endothelial Cell Death: A Predominant Role of Histones. PLoS ONE 2012, 7, e32366.
  146. Nicholls, S.J.; Hazen, S.L. Myeloperoxidase, Modified Lipoproteins, and Atherogenesis. J. Lipid Res. 2009, 50, S346–S351.
  147. Alfaidi, M.; Wilson, H.; Daigneault, M.; Burnett, A.; Ridger, V.; Chamberlain, J.; Francis, S. Neutrophil Elastase Promotes Interleukin-1β Secretion from Human Coronary Endothelium. J. Biol. Chem. 2015, 290, 24067–24078.
  148. Metzler, K.D.; Fuchs, T.A.; Nauseef, W.M.; Reumaux, D.; Roesler, J.; Schulze, I.; Wahn, V.; Papayannopoulos, V.; Zychlinsky, A. Myeloperoxidase Is Required for Neutrophil Extracellular Trap Formation: Implications for Innate Immunity. Blood 2011, 117, 953–959.
  149. Metzler, K.D.; Goosmann, C.; Lubojemska, A.; Zychlinsky, A.; Papayannopoulos, V. A Myeloperoxidase-Containing Complex Regulates Neutrophil Elastase Release and Actin Dynamics during NETosis. Cell Rep. 2014, 8, 883–896.
  150. Brodsky, S.V.; Zhang, F.; Nasjletti, A.; Goligorsky, M.S. Endothelium-Derived Microparticles Impair Endothelial Function in Vitro. Am. J. Physiol. Heart Circ. Physiol. 2004, 286, H1910–H1915.
  151. Awasthi, D.; Nagarkoti, S.; Kumar, A.; Dubey, M.; Singh, A.K.; Pathak, P.; Chandra, T.; Barthwal, M.K.; Dikshit, M. Oxidized LDL Induced Extracellular Trap Formation in Human Neutrophils via TLR-PKC-IRAK-MAPK and NADPH-Oxidase Activation. Free Radic. Biol. Med. 2016, 93, 190–203.
  152. Warnatsch, A.; Ioannou, M.; Wang, Q.; Papayannopoulos, V. Inflammation. Neutrophil Extracellular Traps License Macrophages for Cytokine Production in Atherosclerosis. Science 2015, 349, 316–320.
  153. Smith, C.K.; Vivekanandan-Giri, A.; Tang, C.; Knight, J.S.; Mathew, A.; Padilla, R.L.; Gillespie, B.W.; Carmona-Rivera, C.; Liu, X.; Subramanian, V.; et al. Neutrophil Extracellular Trap-Derived Enzymes Oxidize High-Density Lipoprotein: An Additional Proatherogenic Mechanism in Systemic Lupus Erythematosus. Arthritis Rheumatol. 2014, 66, 2532–2544.
  154. Sharma, S.; Hofbauer, T.M.; Ondracek, A.S.; Chausheva, S.; Alimohammadi, A.; Artner, T.; Panzenboeck, A.; Rinderer, J.; Shafran, I.; Mangold, A.; et al. Neutrophil Extracellular Traps Promote Fibrous Vascular Occlusions in Chronic Thrombosis. Blood 2021, 137, 1104–1116.
  155. Mangold, A.; Alias, S.; Scherz, T.; Hofbauer, T.; Jakowitsch, J.; Panzenböck, A.; Simon, D.; Laimer, D.; Bangert, C.; Kammerlander, A.; et al. Coronary Neutrophil Extracellular Trap Burden and Deoxyribonuclease Activity in ST-Elevation Acute Coronary Syndrome Are Predictors of ST-Segment Resolution and Infarct Size. Circ. Res. 2015, 116, 1182–1192.
  156. Gillum, R.F. Epidemiology of Aortic Aneurysm in the United States. J. Clin. Epidemiol. 1995, 48, 1289–1298.
  157. Al-Balah, A.; Goodall, R.; Salciccioli, J.D.; Marshall, D.C.; Shalhoub, J. Mortality from Abdominal Aortic Aneurysm: Trends in European Union 15+ Countries from 1990 to 2017. Br. J. Surg. 2020, 107, 1459–1467.
  158. Treska, V.; Kocova, J.; Boudova, L.; Neprasova, P.; Topolcan, O.; Pecen, L.; Tonar, Z. Inflammation in the Wall of Abdominal Aortic Aneurysm and Its Role in the Symptomatology of Aneurysm. Cytokines Cell Mol. Ther. 2002, 7, 91–97.
  159. Beckman, E.N. Plasma Cell Infiltrates in Atherosclerotic Abdominal Aortic Aneurysms. Am. J. Clin. Pathol. 1986, 85, 21–24.
  160. Newmans, K.M.; Malon, A.M.; Shin, R.D.; Scholes, J.V.; Ramey, W.G.; Tilson, M.D. Matrix Metalloproteinases in Abdominal Aortic Aneurysm: Characterization, Purification, and Their Possible Sources. Connect. Tissue Res. 1994, 30, 265–276.
  161. Reilly, J.M.; Brophy, C.M.; Tilson, M.D. Characterization of an Elastase from Aneurysmal Aorta Which Degrades Intact Aortic Elastin. Ann. Vasc. Surg. 1992, 6, 499–502.
  162. Brown, P.M.; Zelt, D.T.; Sobolev, B.; Hallett, J.W.; Sternbach, Y. The Risk of Rupture in Untreated Aneurysms: The Impact of Size, Gender, and Expansion Rate. J. Vasc. Surg. 2003, 37, 280–284.
  163. Chaikof, E.L.; Dalman, R.L.; Eskandari, M.K.; Jackson, B.M.; Lee, W.A.; Mansour, M.A.; Mastracci, T.M.; Mell, M.; Murad, M.H.; Nguyen, L.L.; et al. The Society for Vascular Surgery Practice Guidelines on the Care of Patients with an Abdominal Aortic Aneurysm. J. Vasc. Surg. 2018, 67, 2–77.e2.
  164. Brady, A.R.; Thompson, S.G.; Fowkes, F.G.R.; Greenhalgh, R.M.; Powell, J.T. Abdominal Aortic Aneurysm Expansion: Risk Factors and Time Intervals for Surveillance. Circulation 2004, 110, 16–21.
  165. Kronmal, R.A.; McClelland, R.L.; Detrano, R.; Shea, S.; Lima, J.A.; Cushman, M.; Bild, D.E.; Burke, G.L. Risk Factors for the Progression of Coronary Artery Calcification in Asymptomatic Subjects. Circulation 2007, 115, 2722–2730.
  166. Liabeuf, S.; Olivier, B.; Vemeer, C.; Theuwissen, E.; Magdeleyns, E.; Aubert, C.E.; Brazier, M.; Mentaverri, R.; Hartemann, A.; Massy, Z.A. Vascular Calcification in Patients with Type 2 Diabetes: The Involvement of Matrix Gla Protein. Cardiovasc. Diabetol. 2014, 13, 85.
  167. Leow, K.; Szulc, P.; Schousboe, J.T.; Kiel, D.P.; Teixeira-Pinto, A.; Shaikh, H.; Sawang, M.; Sim, M.; Bondonno, N.; Hodgson, J.M.; et al. Prognostic Value of Abdominal Aortic Calcification: A Systematic Review and Meta-Analysis of Observational Studies. J. Am. Heart Assoc. 2021, 10, e017205.
  168. Rossi, A.; Targher, G.; Zoppini, G.; Cicoira, M.; Bonapace, S.; Negri, C.; Stoico, V.; Faggiano, P.; Vassanelli, C.; Bonora, E. Aortic and Mitral Annular Calcifications Are Predictive of All-Cause and Cardiovascular Mortality in Patients with Type 2 Diabetes. Diabetes Care 2012, 35, 1781–1786.
  169. Niu, W.; Shao, J.; Yu, B.; Liu, G.; Wang, R.; Dong, H.; Che, H.; Li, L. Association Between Metformin and Abdominal Aortic Aneurysm: A Meta-Analysis. Front. Cardiovasc. Med. 2022, 9, 908747.
  170. Limiting AAA with Metformin (LIMIT) Trial—Full Text View—ClinicalTrials.gov. Available online: https://clinicaltrials.gov/ct2/show/NCT04500756?cond=abdominal+aortic+aneurysm+metformin&draw=2&rank=3 (accessed on 5 March 2023).
  171. Metformin Therapy in Non-Diabetic AAA Patients—Full Text View—ClinicalTrials.gov. Available online: https://clinicaltrials.gov/ct2/show/NCT03507413?cond=abdominal+aortic+aneurysm+metformin&draw=2&rank=1 (accessed on 5 March 2023).
  172. Metformin for Abdominal Aortic Aneurysm Growth Inhibition—Full Text View—ClinicalTrials.gov. Available online: https://clinicaltrials.gov/ct2/show/NCT04224051?cond=abdominal+aortic+aneurysm+metformin&draw=2&rank=2 (accessed on 5 March 2023).
  173. Klopf, J.; Fuchs, L.; Schernthaner, R.; Domenig, C.M.; Gollackner, B.; Brostjan, C.; Neumayer, C.; Eilenberg, W. The Prognostic Impact of Vascular Calcification on Abdominal Aortic Aneurysm Progression. J. Vasc. Surg. 2022, 75, 1926–1934.
  174. Kent, K.C.; Zwolak, R.M.; Egorova, N.N.; Riles, T.S.; Manganaro, A.; Moskowitz, A.J.; Gelijns, A.C.; Greco, G. Analysis of Risk Factors for Abdominal Aortic Aneurysm in a Cohort of More than 3 Million Individuals. J. Vasc. Surg. 2010, 52, 539–548.
  175. Ito, S.; Akutsu, K.; Tamori, Y.; Sakamoto, S.; Yoshimuta, T.; Hashimoto, H.; Takeshita, S. Differences in Atherosclerotic Profiles Between Patients with Thoracic and Abdominal Aortic Aneurysms. Am. J. Cardiol. 2008, 101, 696–699.
  176. Sun, W.; Zheng, J.; Gao, Y. Targeting Platelet Activation in Abdominal Aortic Aneurysm: Current Knowledge and Perspectives. Biomolecules 2022, 12, 206.
  177. Libby, P.; Ridker, P.M.; Maseri, A. Inflammation and Atherosclerosis. Circulation 2002, 105, 1135–1143.
  178. Raffort, J.; Lareyre, F.; Clément, M.; Hassen-Khodja, R.; Chinetti, G.; Mallat, Z. Monocytes and Macrophages in Abdominal Aortic Aneurysm. Nat. Rev. Cardiol. 2017, 14, 457–471.
  179. Houard, X.; Touat, Z.; Ollivier, V.; Louedec, L.; Philippe, M.; Sebbag, U.; Meilhac, O.; Rossignol, P.; Michel, J.B. Mediators of Neutrophil Recruitment in Human Abdominal Aortic Aneurysms. Cardiovasc. Res. 2009, 82, 532–541.
  180. Thompson, R.W.; Curci, J.A.; Ennis, T.L.; Mao, D.; Pagano, M.B.; Pham, C.T.N. Pathophysiology of Abdominal Aortic Aneurysms: Insights from the Elastase-Induced Model in Mice with Different Genetic Backgrounds. Ann. N. Y. Acad. Sci. 2006, 1085, 59–73.
  181. Rao, J.; Brown, B.N.; Weinbaum, J.S.; Ofstun, E.L.; Makaroun, M.S.; Humphrey, J.D.; Vorp, D.A. Distinct Macrophage Phenotype and Collagen Organization within the Intraluminal Thrombus of Abdominal Aortic Aneurysm. J. Vasc. Surg. 2015, 62, 585–593.
  182. Dutertre, C.A.; Clement, M.; Morvan, M.; Schäkel, K.; Castier, Y.; Alsac, J.M.; Michel, J.B.; Nicoletti, A. Deciphering the Stromal and Hematopoietic Cell Network of the Adventitia from Non-Aneurysmal and Aneurysmal Human Aorta. PLoS ONE 2014, 9, e89983.
  183. Tieu, B.C.; Ju, X.; Lee, C.; Sun, H.; Lejeune, W.; Recinos, A.; Brasier, A.R.; Tilton, R.G. Aortic Adventitial Fibroblasts Participate in Angiotensin-Induced Vascular Wall Inflammation and Remodeling. J. Vasc. Res. 2011, 48, 261–272.
  184. Tieu, B.C.; Lee, C.; Sun, H.; LeJeune, W.; Recinos, A.; Ju, X.; Spratt, H.; Guo, D.C.; Milewicz, D.; Tilton, R.G.; et al. An Adventitial IL-6/MCP1 Amplification Loop Accelerates Macrophage-Mediated Vascular Inflammation Leading to Aortic Dissection in Mice. J. Clin. Investig. 2009, 119, 3637–3651.
  185. Combadière, C.; Potteaux, S.; Rodero, M.; Simon, T.; Pezard, A.; Esposito, B.; Merval, R.; Proudfoot, A.; Tedgui, A.; Mallat, Z. Combined Inhibition of CCL2, CX3CR1, and CCR5 Abrogates Ly6C(Hi) and Ly6C(Lo) Monocytosis and Almost Abolishes Atherosclerosis in Hypercholesterolemic Mice. Circulation 2008, 117, 1649–1657.
  186. Daugherty, A.; Manning, M.W.; Cassis, L.A. Angiotensin II Promotes Atherosclerotic Lesions and Aneurysms in Apolipoprotein E-Deficient Mice. J. Clin. Investig. 2000, 105, 1605–1612.
  187. Deshmane, S.L.; Kremlev, S.; Amini, S.; Sawaya, B.E. Monocyte Chemoattractant Protein-1 (MCP-1): An Overview. J. Interferon Cytokine Res. 2009, 29, 313–326.
  188. Zhang, H.; Yang, K.; Chen, F.; Liu, Q.; Ni, J.; Cao, W.; Hua, Y.; He, F.; Liu, Z.; Li, L.; et al. Role of the CCL2-CCR2 Axis in Cardiovascular Disease: Pathogenesis and Clinical Implications. Front. Immunol. 2022, 13, 975367.
  189. Roshan, M.H.K.; Tambo, A.; Pace, N.P. The Role of TLR2, TLR4, and TLR9 in the Pathogenesis of Atherosclerosis. Int. J. Inflamm. 2016, 2016, 1532832.
  190. Yang, M.; Chen, Q.; Mei, L.; Wen, G.; An, W.; Zhou, X.; Niu, K.; Liu, C.; Ren, M.; Sun, K.; et al. Neutrophil Elastase Promotes Neointimal Hyperplasia by Targeting Toll-like Receptor 4 (TLR4)-NF-ΚB Signalling. Br. J. Pharmacol. 2021, 178, 4048–4068.
  191. Kolaczkowska, E.; Kubes, P. Neutrophil Recruitment and Function in Health and Inflammation. Nat. Rev. Immunol. 2013, 13, 159–175.
  192. Dalli, J.; Montero-Melendez, T.; Norling, L.V.; Yin, X.; Hinds, C.; Haskard, D.; Mayr, M.; Perretti, M. Heterogeneity in Neutrophil Microparticles Reveals Distinct Proteome and Functional Properties. Mol. Cell Proteom. 2013, 12, 2205–2219.
  193. Mortaz, E.; Alipoor, S.D.; Adcock, I.M.; Mumby, S.; Koenderman, L. Update on Neutrophil Function in Severe Inflammation. Front. Immunol. 2018, 9, 2171.
  194. Klopf, J.; Brostjan, C.; Eilenberg, W.; Neumayer, C. Neutrophil Extracellular Traps and Their Implications in Cardiovascular and Inflammatory Disease. Int. J. Mol. Sci. 2021, 22, 559.
  195. Arbănași, E.M.; Mureșan, A.V.; Coșarcă, C.M.; Arbănași, E.M.; Niculescu, R.; Voidăzan, S.T.; Ivănescu, A.D.; Hălmaciu, I.; Filep, R.C.; Mărginean, L.; et al. Computed Tomography Angiography Markers and Intraluminal Thrombus Morphology as Predictors of Abdominal Aortic Aneurysm Rupture. Int. J. Environ. Res. Public Health 2022, 19, 15961.
  196. Behr-Rasmussen, C.; Grøndal, N.; Bramsen, M.B.; Thomsen, M.D.; Lindholt, J.S. Mural Thrombus and the Progression of Abdominal Aortic Aneurysms: A Large Population-Based Prospective Cohort Study. Eur. J. Vasc. Endovasc. Surg. 2014, 48, 301–307.
  197. Kazi, M.; Thyberg, J.; Religa, P.; Roy, J.; Eriksson, P.; Hedin, U.; Swedenborg, J. Influence of Intraluminal Thrombus on Structural and Cellular Composition of Abdominal Aortic Aneurysm Wall. J. Vasc. Surg. 2003, 38, 1283–1292.
  198. Schrottmaier, W.C.; Mussbacher, M.; Salzmann, M.; Assinger, A. Platelet-Leukocyte Interplay during Vascular Disease. Atherosclerosis 2020, 307, 109–120.
  199. Rubenstein, D.A.; Yin, W. Platelet-Activation Mechanisms and Vascular Remodeling. Compr. Physiol. 2018, 8, 1117–1156.
  200. Houard, X.; Ollivier, V.; Louedec, L.; Michel, J.; Back, M. Differential Inflammatory Activity across Human Abdominal Aortic Aneurysms Reveals Neutrophil-Derived Leukotriene B4 as a Major Chemotactic Factor Released from the Intraluminal Thrombus. FASEB J. 2009, 23, 1376–1383.
  201. Karaolanis, G.; Moris, D.; Palla, V.V.; Karanikola, E.; Bakoyiannis, C.; Georgopoulos, S. Neutrophil Gelatinase Associated Lipocalin (NGAL) as a Biomarker. Does It Apply in Abdominal Aortic Aneurysms? A Review of Literature. Indian J. Surg. 2015, 77 (Suppl. S3), 1313–1317.
  202. Petersen, E.; Wågberg, F.; Ängquist, K.A. Serum Concentrations of Elastin-Derived Peptides in Patients with Specific Manifestations of Atherosclerotic Disease. Eur. J. Vasc. Endovasc. Surg. 2002, 24, 440–444.
  203. Maguire, E.M.; Pearce, S.W.A.; Xiao, R.; Oo, A.Y.; Xiao, Q. Matrix Metalloproteinase in Abdominal Aortic Aneurysm and Aortic Dissection. Pharmaceuticals 2019, 12, 118.
  204. Hendy, K.; Gunnarson, R.; Golledge, J. Growth Rates of Small Abdominal Aortic Aneurysms Assessed by Computerised Tomography—A Systematic Literature Review. Atherosclerosis 2014, 235, 182–188.
  205. Selders, G.S.; Fetz, A.E.; Radic, M.Z.; Bowlin, G.L. An Overview of the Role of Neutrophils in Innate Immunity, Inflammation and Host-Biomaterial Integration. Regen. Biomater. 2017, 4, 55–68.
  206. Yan, H.; Zhou, H.F.; Akk, A.; Hu, Y.; Springer, L.E.; Ennis, T.L.; Pham, C.T.N. Neutrophil Proteases Promote Experimental Abdominal Aortic Aneurysm via Extracellular Trap Release and Plasmacytoid Dendritic Cell Activation. Arter. Thromb. Vasc. Biol. 2016, 36, 1660–1669.
  207. Delbosc, S.; Alsac, J.M.; Journe, C.; Louedec, L.; Castier, Y.; Bonnaure-Mallet, M.; Ruimy, R.; Rossignol, P.; Bouchard, P.; Michel, J.B.; et al. Porphyromonas Gingivalis Participates in Pathogenesis of Human Abdominal Aortic Aneurysm by Neutrophil Activation. Proof of Concept in Rats. PLoS ONE 2011, 6, e18679.
  208. Jabłońska, A.; Zagrapan, B.; Paradowska, E.; Neumayer, C.; Eilenberg, W.; Brostjan, C.; Klinger, M.; Nanobachvili, J.; Huk, I. Abdominal Aortic Aneurysm and Virus Infection: A Potential Causative Role for Cytomegalovirus Infection? J. Med. Virol. 2021, 93, 5017–5024.
  209. Mysak, J.; Podzimek, S.; Sommerova, P.; Lyuya-Mi, Y.; Bartova, J.; Janatova, T.; Prochazkova, J.; Duskova, J. Porphyromonas Gingivalis: Major Periodontopathic Pathogen Overview. J. Immunol. Res. 2014, 2014, 476068.
  210. Salhi, L.; Rijkschroeff, P.; Van Hede, D.; Laine, M.L.; Teughels, W.; Sakalihasan, N.; Lambert, F. Blood Biomarkers and Serologic Immunological Profiles Related to Periodontitis in Abdominal Aortic Aneurysm Patients. Front. Cell Infect. Microbiol. 2022, 11, 766462.
  211. Salhi, L.; Sakalihasan, N.; Okroglic, A.G.; Labropoulos, N.; Seidel, L.; Albert, A.; Teughels, W.; Defraigne, J.O.; Lambert, F. Further Evidence on the Relationship between Abdominal Aortic Aneurysm and Periodontitis: A Cross-Sectional Study. J. Periodontol. 2020, 91, 1453–1464.
  212. Salhi, L.; Rompen, E.; Sakalihasan, N.; Laleman, I.; Teughels, W.; Michel, J.B.; Lambert, F. Can Periodontitis Influence the Progression of Abdominal Aortic Aneurysm? A Systematic Review. Angiology 2019, 70, 479–491.
  213. Gredmark-Russ, S.; Dzabic, M.; Rahbar, A.; Wanhainen, A.; Björck, M.; Larsson, E.; Michel, J.B.; Söderberg-Nauclér, C. Active Cytomegalovirus Infection in Aortic Smooth Muscle Cells from Patients with Abdominal Aortic Aneurysm. J. Mol. Med. 2009, 87, 347–356.
  214. Pinard, A.; Jones, G.T.; Milewicz, D.M. Genetics of Thoracic and Abdominal Aortic Diseases: Aneurysms, Dissections, and Ruptures. Circ. Res. 2019, 124, 588.
  215. La Rocca, G.; Del Frate, G.; Delvino, P.; Di Cianni, F.; Moretti, M.; Italiano, N.; Treppo, E.; Monti, S.; Talarico, R.; Ferro, F.; et al. Systemic Vasculitis: One Year in Review 2022. Clin. Exp. Rheumatol. 2022, 40, 673–687.
  216. Phillip, R.; Luqmani, R. Mortality in Systemic Vasculitis: A Systematic Review. Clin. Exp. Rheumatol. 2008, 26 (Suppl. S51), S94–S104.
  217. Wallace, Z.S.; Fu, X.; Harkness, T.; Stone, J.H.; Zhang, Y.; Choi, H. All-Cause and Cause-Specific Mortality in ANCA-Associated Vasculitis: Overall and According to ANCA Type. Rheumatology 2020, 59, 2308–2315.
  218. Hill, C.L.; Black, R.J.; Nossent, J.C.; Ruediger, C.; Nguyen, L.; Ninan, J.V.; Lester, S. Risk of Mortality in Patients with Giant Cell Arteritis: A Systematic Review and Meta-Analysis. Semin. Arthritis Rheum. 2017, 46, 513–519.
  219. Mueller, M.; Gschwandtner, M.E.; Gamper, J.; Giurgea, G.A.; Kiener, H.P.; Perkmann, T.; Koppensteiner, R.; Schlager, O. Chronic Inflammation Predicts Long-Term Mortality in Patients with Raynaud’s Phenomenon. J. Intern. Med. 2018, 283, 293–302.
  220. Chironi, G.; Pagnoux, C.; Simon, A.; Pasquinelli-Balice, M.; Del-Pino, M.; Gariepy, J.; Guillevin, L. Increased Prevalence of Subclinical Atherosclerosis in Patients with Small-Vessel Vasculitis. Heart 2007, 93, 96–99.
  221. Farrah, T.E.; Melville, V.; Czopek, A.; Fok, H.; Bruce, L.; Mills, N.L.; Bailey, M.A.; Webb, D.J.; Dear, J.W.; Dhaun, N. Arterial Stiffness, Endothelial Dysfunction and Impaired Fibrinolysis Are Pathogenic Mechanisms Contributing to Cardiovascular Risk in ANCA-Associated Vasculitis. Kidney Int. 2022, 102, 1115–1126.
  222. Clifford, A.H.; Cohen Tervaert, J.W. Cardiovascular Events and the Role of Accelerated Atherosclerosis in Systemic Vasculitis. Atherosclerosis 2021, 325, 8–15.
  223. Hilhorst, M.; Winckers, K.; Wilde, B.; Van Oerle, R.; Ten Cate, H.; Tervaert, J.W.C. Patients with Antineutrophil Cytoplasmic Antibodies Associated Vasculitis in Remission Are Hypercoagulable. J. Rheumatol. 2013, 40, 2042–2046.
  224. De Leeuw, K.; Sanders, J.S.; Stegeman, C.; Smit, A.; Kallenberg, C.G.; Bijl, M. Accelerated Atherosclerosis in Patients with Wegener’s Granulomatosis. Ann. Rheum. Dis. 2005, 64, 753–759.
  225. Shirai, T.; Hilhorst, M.; Harrison, D.G.; Goronzy, J.J.; Weyand, C.M. Macrophages in Vascular Inflammation--From Atherosclerosis to Vasculitis. Autoimmunity 2015, 48, 139–151.
  226. Wallace, Z.S.; Fu, X.; Liao, K.; Kallenberg, C.G.M.; Langford, C.A.; Merkel, P.A.; Monach, P.; Seo, P.; Specks, U.; Spiera, R.; et al. Disease Activity, Antineutrophil Cytoplasmic Antibody Type, and Lipid Levels in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. Arthritis Rheumatol. 2019, 71, 1879–1887.
  227. Proven, A.; Gabriel, S.E.; Orces, C.; Michael O’Fallon, W.; Hunder, G.G. Glucocorticoid Therapy in Giant Cell Arteritis: Duration and Adverse Outcomes. Arthritis Rheum. 2003, 49, 703–708.
  228. Bramlage, C.P.; Kröplin, J.; Wallbach, M.; Minguet, J.; Smith, K.H.; Lüders, S.; Schrader, J.; Patschan, S.; Gross, O.; Deutsch, C.; et al. Management of Cardiovascular Risk Factors in Patients with ANCA-Associated Vasculitis. J. Eval. Clin. Pract. 2017, 23, 747–754.
  229. Ytterberg, S.R.; Bhatt, D.L.; Mikuls, T.R.; Koch, G.G.; Fleischmann, R.; Rivas, J.L.; Germino, R.; Menon, S.; Sun, Y.; Wang, C.; et al. Cardiovascular and Cancer Risk with Tofacitinib in Rheumatoid Arthritis. N. Engl. J. Med. 2022, 386, 316–326.
  230. Smolen, J.S.; Landewé, R.B.M.; Bergstra, S.A.; Kerschbaumer, A.; Sepriano, A.; Aletaha, D.; Caporali, R.; Edwards, C.J.; Hyrich, K.L.; Pope, J.E.; et al. EULAR Recommendations for the Management of Rheumatoid Arthritis with Synthetic and Biological Disease-Modifying Antirheumatic Drugs: 2022 Update. Ann. Rheum. Dis. 2023, 82, 3–18.
  231. Ertus, C.; Scailteux, L.-M.; Lescoat, A.; Berthe, P.; Auffret, V.; Dupuy, A.; Oger, E.; Droitcourt, C. Major Adverse Cardiovascular Events in Patients Treated with Oral Janus Kinase Inhibitors for Atopic Dermatitis: A Systematic Review and Meta-Analysis. Br. J. Dermatol. 2023, 6, ljad229.
  232. Hoisnard, L.; Pina Vegas, L.; Dray-Spira, R.; Weill, A.; Zureik, M.; Sbidian, E. Risk of Major Adverse Cardiovascular and Venous Thromboembolism Events in Patients with Rheumatoid Arthritis Exposed to JAK Inhibitors versus Adalimumab: A Nationwide Cohort Study. Ann. Rheum. Dis. 2023, 82, 182–188.
  233. Cooke, J.P. Inflammation and Its Role in Regeneration and Repair: A Caution for Novel Anti-Inflammatory Therapies. Circ. Res. 2019, 124, 1166.
  234. Mantsounga, C.S.; Lee, C.; Neverson, J.; Sharma, S.; Healy, A.; Berus, J.M.; Parry, C.; Ceneri, N.M.; López-Giráldez, F.; Chun, H.J.; et al. Macrophage IL-1β Promotes Arteriogenesis by Autocrine STAT3- and NF-ΚB-Mediated Transcription of pro-Angiogenic VEGF-A. Cell Rep. 2022, 38, 110309.
  235. Heil, M.; Eitenmüller, I.; Schmitz-Rixen, T.; Schaper, W. Arteriogenesis versus Angiogenesis: Similarities and Differences. J. Cell Mol. Med. 2006, 10, 45.
  236. Wang, G.L.; Jiang, B.H.; Rue, E.A.; Semenza, G.L. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc. Natl. Acad. Sci. USA 1995, 92, 5510–5514.
  237. Heil, M.; Ziegelhoeffer, T.; Wagner, S.; Fernández, B.; Helisch, A.; Martin, S.; Tribulova, S.; Kuziel, W.A.; Bachmann, G.; Schaper, W. Collateral Artery Growth (Arteriogenesis) after Experimental Arterial Occlusion Is Impaired in Mice Lacking CC-Chemokine Receptor-2. Circ. Res. 2004, 94, 671–677.
  238. Heuslein, J.L.; Meisner, J.K.; Li, X.; Song, J.; Vincentelli, H.; Leiphart, R.J.; Ames, E.G.; Blackman, B.R.; Price, R.J. Mechanisms of Amplified Arteriogenesis in Collateral Artery Segments Exposed to Flow Direction Reversal. Arter. Thromb. Vasc. Biol. 2015, 35, 2354.
  239. Mantovani, A.; Garlanda, C.; Locati, M. Macrophage Diversity and Polarization in Atherosclerosis: A Question of Balance. Arter. Thromb. Vasc. Biol. 2009, 29, 1419–1423.
  240. Voronov, E.; Shouval, D.S.; Krelin, Y.; Cagnano, E.; Benharroch, D.; Iwakura, Y.; Dinarello, C.A.; Apte, R.N. IL-1 Is Required for Tumor Invasiveness and Angiogenesis. Proc. Natl. Acad. Sci. USA 2003, 100, 2645.
  241. Amano, K.; Okigaki, M.; Adachi, Y.; Fujiyama, S.; Mori, Y.; Kosaki, A.; Iwasaka, T.; Matsubara, H. Mechanism for IL-1β-Mediated Neovascularization Unmasked by IL-1β Knock-out Mice. J. Mol. Cell Cardiol. 2004, 36, 469–480.
More
Information
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register : , , , , , , , ,
View Times: 172
Revisions: 2 times (View History)
Update Date: 07 Sep 2023
1000/1000
Video Production Service