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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: (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: 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, (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.
Poledniczek, Michael, et al. "Pathophysiology of Inflammation in Peripheral Artery Disease." Encyclopedia. Web. 05 September, 2023.
Pathophysiology of Inflammation in Peripheral Artery Disease

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] .


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