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Immanuel, J.; Yun, S. Vascular Inflammatory Diseases and Endothelial Phenotypes. Encyclopedia. Available online: https://encyclopedia.pub/entry/46041 (accessed on 29 June 2024).
Immanuel J, Yun S. Vascular Inflammatory Diseases and Endothelial Phenotypes. Encyclopedia. Available at: https://encyclopedia.pub/entry/46041. Accessed June 29, 2024.
Immanuel, Jenita, Sanguk Yun. "Vascular Inflammatory Diseases and Endothelial Phenotypes" Encyclopedia, https://encyclopedia.pub/entry/46041 (accessed June 29, 2024).
Immanuel, J., & Yun, S. (2023, June 26). Vascular Inflammatory Diseases and Endothelial Phenotypes. In Encyclopedia. https://encyclopedia.pub/entry/46041
Immanuel, Jenita and Sanguk Yun. "Vascular Inflammatory Diseases and Endothelial Phenotypes." Encyclopedia. Web. 26 June, 2023.
Vascular Inflammatory Diseases and Endothelial Phenotypes
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This entry is adapted from the peer-reviewed paper 10.3390/cells12121640

The physiological functions of endothelial cells control vascular tone, permeability, inflammation, and angiogenesis, which significantly help to maintain a healthy vascular system. Several cardiovascular diseases are characterized by endothelial cell activation or dysfunction triggered by external stimuli such as disturbed flow, hypoxia, growth factors, and cytokines in response to high levels of low-density lipoprotein and cholesterol, hypertension, diabetes, aging, drugs, and smoking. Increasing evidence suggests that uncontrolled proinflammatory signaling and further alteration in endothelial cell phenotypes such as barrier disruption, increased permeability, endothelial to mesenchymal transition (EndMT), and metabolic reprogramming further induce vascular diseases, and multiple studies are focusing on finding the pathways and mechanisms involved in it.

endothelial cell inflammation EC phenotypes vascular disease

1. Introduction

Endothelial cells line the luminal surface and act as a barrier separating blood and surrounding tissue. Its dynamic and heterogeneous structure influences various important processes, such as vascular permeability, homeostasis, angiogenesis, metabolism, inflammatory cell trafficking, vasomotor tone, and immunity [1][2][3]. Remarkably, its well-defined barrier structure prevents extravasation of liquids, ions, chemicals, and leukocytes, and signaling pathways are functionally aligned according to the demands under certain conditions. Intercellular junctions regulate endothelial permeability with the help of junctional protein complexes called adherens junctions (AJs), gap junctions (GJs), tight junctions (TJs), and other adhesion receptors, such as platelet-endothelial cell adhesion molecule-1(PECAM-1) [4][5][6]. In regulating vascular tone, the endothelium plays a crucial role by releasing a variety of relaxing factors, including nitric oxide (NO), endothelium-dependent hyperpolarization factors, and vasodilator prostaglandins. NO is a critical component of a healthy vascular endothelium and helps keep the vascular wall in a quiescent state by preventing thrombosis, cellular proliferation, and inflammation. This quiescent, NO-dominated endothelium phenotype is most likely maintained by laminar shear stress [7][8].
Vascular disease is a result of endothelial dysfunction, which is often referred to as endothelial activation in pathological situations. A change from a quiescent phenotype to one that engages the host defense response is represented by endothelial activation. In fact, the majority of cardiovascular risk factors trigger endothelium-based molecular machinery, causing the expression of chemokines, cytokines, and adhesion molecules that are intended to interact with leukocytes and platelets and target inflammation in specific sites to eliminate pathogens. The basic change occurring in this process is a shift in the signaling from NO-mediated silencing of cellular processes to redox-mediated activation through reactive oxygen species (ROS) [9]. It is noteworthy that NO, which generally aids in retaining the endothelium in a quiescent state, can be converted to ROS under certain conditions as part of endothelial activation, which is called eNOS uncoupling. Endothelial functions are crucial for ensuring the appropriate maintenance of vascular homeostasis. Depending on the type, severity, duration, and combination of the proinflammatory stimuli, endothelial activation and redox signaling may promote host defense or trigger vascular inflammatory diseases. Increasing evidence suggests that endothelial dysfunction is a hallmark of a variety of cardiovascular conditions associated with pathological states including vasoconstriction, leukocyte adhesion, thrombosis, and inflammatory state.

2. Endothelial Proinflammatory Phenotype

Endothelial cells in healthy resting vasculatures contribute to vascular homeostasis by keeping vascular inflammation, thrombosis, and permeability low. Under various EC-activating stimuli, endothelial cells undergo phenotypic changes to meet the needs for immune cell recruitment or new vessel formation. During infection, endothelial cells exhibit proinflammatory phenotypes to fight pathogens. However, uncontrolled inflammation can damage host tissue and lead to various vascular inflammatory diseases. The phenotypic changes occurring in ECs during vascular inflammation are discussed below.

2.1. Cell Surface Adhesion Molecule Expression

Endothelial inflammatory signaling triggered by inflammatory stimuli leads to the expression and cell surface localization of cell adhesion molecules (CAMs). The main function of CAMs is to facilitate leukocyte infiltration from the blood stream into the inflamed tissues. Vascular cell adhesion molecules-1 (VCAM-1) and intercellular adhesion molecules-1 (ICAM-1) are well-known transcriptional targets of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Yes-associated proteins (Yap) [10]. Their surface expressions are upregulated in ECs during inflammation and involved in leukocyte adhesion and rolling [11]. JAM molecules (JAM-A, JAM-B, and JAM-C) are mediators of leukocyte–EC and platelet–EC interaction via heterophilic trans-interactions [12]. Under resting conditions, homophilic trans-interactions of JAM-A contribute to TJ formation. However, under inflammatory conditions, junctional JAM-A mobilizes to the apical side for leukocyte binding. Selectins are a family of three C-type lectins expressed by bone-marrow-derived cells and endothelial cells [13]. Selectins have a carbohydrate recognition domain that binds specific glycans on leukocytes [14]. ECs express E-selectin and P-selectin. Chemokines are low-molecular-weight peptides that often act as chemotactic factors in inflammation, and they comprise four groups (CXC, CC, C, and CX3C) depending on the number and spacing of conserved cysteines. ECs secrete numerous chemokines and also express chemokine receptors on their surfaces [15]. Ox-LDL or disturbed flow induce monocyte chemoattractant protein-1 (MCP-1) expression on the vascular wall, which mediates monocyte recruitment and atherosclerosis through the interaction between CCL2 on MCP-1 and CCR2 on monocytes [16].

2.2. Increased Endothelial Permeability

Endothelial permeability can be categorized into paracellular permeability and transcellular permeability. Paracellular permeability increases when tight junction (TJ) or adherens junction (AJ) mediated by homophilic adhesion molecules such as VE-cadherin, Occludin, or Claudin are disrupted. Transcellular permeability refers to the passage of molecules (transcytosis) or immune cells (transcellular migration) across plasma membranes via endocytic pathways. Under neuroinflammation, Th1 cells use a transcellular migration pathway, whereas Th17 cells use paracellular pores formed by TJ remodeling for CNS entry [17]. Another finding has shown that CNS endothelial cells have a specific mechanism inhibiting caveolae-mediated transcytosis, which promotes BBB integrity [18]. EC barrier function is compromised in various vascular inflammatory conditions. In infections, an increase in permeability is required for the recruitment of circulating leukocytes to the tissue area via a process called diapedesis [19]. Under pathological conditions, uncontrolled inflammation and vascular leakage often become detrimental due to fluid leakage into tissues, inducing edema and organ dysfunction. Inflammatory insults lead to VE-cadherin-mediated cell–cell junction disruption by src-dependent tyrosine phosphorylation [19] and the internalization of VE-cadherin. Disassembled junctions promote transendothelial migration (TEM) of monocytes to the subendothelial area [20]. A molecular weight of greater than 50,000 prevents extravasation under resting conditions, but not under inflammation or tumors [21][22] In early atherosclerosis, LDLs accumulate in the subendothelial region via transcytosis [23][24]. Fibrinogen extravasation in an inflamed Alzheimer’s disease brain contributes to neuronal damage in AD patients [25].

2.3. EndMT

A recent analysis revealed that atherosclerotic plaque has EC-derived mesenchymal cells, which increase in number as atherosclerosis progresses [26]. In vivo lineage tracing experiments showed that approximately 30% of aortic ECs express mesenchymal markers NOTC3 or FAP in hyperlipidemia mouse models via EndMT process [27][28]. Endothelial-to-mesenchymal transition (EndMT) refers to the transition of endothelial cells into less-differentiated mesenchymal cell types [29]. EndMT involves the loss of cell–cell junction, fibroblast-like cell morphology, and fibrosis [26]. Inflammatory ligands IL1b, TGF-β, and TNF-𝛼 and disturbed flow are known EndMT-inducing stimuli. Endothelial cells that endure EndMT cease to express EC-specific proteins such as vascular epidermal growth factor receptor (VEGFR), CD31/(PECAM-1), and vascular endothelial cadherin (VE-cadherin) and begin to express and produce mesenchymal-cell-specific proteins such as α-smooth muscle actin (α-SMA), vimentin, fibronectin, N-cadherin, fibroblast-specific protein-1 (FSP-1), fibroblast activating protein (FAP), and fibrillar collagens. Numerous studies have demonstrated that the TGF-β family of growth factors are the primary inducers of EndMT. However, EndMT is a highly complex process that involves a wide range of TGF-β and non-TGF-β signaling pathways and is regulated by a number of molecular processes depending on the health or pathological status of the cells as well as their unique cellular environment. TGF-β signaling mainly induces EndMT through SMAD 2/3 phosphorylation. Several other non-TGF-β signaling mechanisms, such as MAPK, PI3K, and PKC-δ, also induce EndMT. Previous studies reported that oscillatory shear stress promotes the activation of BMP, FGF, NOTCH, WNT, and ET-1, increasing mesenchymal markers through transcription factors SNAI1 and TWIST [30][31].

2.4. Senescence

Cellular senescence is a state of permanent cell cycle arrest due to various stresses [32]. Inflammation, oxidative stress, and disturbed flow have been known to induce premature endothelial senescence [32][33]. Senescence leads to endothelial dysfunction and arterial stiffness, thus contributing to cardiovascular diseases such as atherosclerosis.

3. Vascular Inflammatory Diseases

3.1. Atherosclerosis

Atherosclerosis is a chronic inflammatory disease. A healthy endothelium actively reduces thrombosis, vascular inflammation, and hypertrophy in addition to mediating endothelium-dependent vasodilation. Endothelial dysfunction and inflammation are responsible for various pathologies involved in atherosclerosis.

3.1.1. Plaque Instability and Endothelium

Recent clinical data indicate that plaque disruption rather than plaque stenosis is related to cardiovascular events and mortality in patients [34]. Unstable plaques feature a large necrotic core, high macrophage content, and thin fibrous cap [35]. Evidence indicates plaque destabilization is caused by inflammation due to immune cell infiltration in atherosclerotic lesions. Matrix degradation and apoptosis, two crucial factors in plaque stability, are controlled by inflammatory mediators from macrophages and T cells. Owen’s group recently revealed that ACTA2+ myofibroblast-like cells originate not only from smooth muscle cells but also from endothelial cells and macrophages via EndMT and macrophage-to-mesenchymal transition (MMT), respectively [36]. Another study supports that control of EndMT could be a valid strategy for plaque stabilization. Kovacic et al. examined histone post-translational modification during EndMT and found that histone deacetylation by HDAC9 is increased. Inhibition of class IIa HDAC family members, blocked-EndMT-mediated gene induction, and endothelial HDAC9 knockout reduced atherosclerosis and enhanced plaque stability [37]. OCT4, a Yamanaka factor, was recently found to be activated in ECs during atherogenesis and plays an important role in plaque stability. Endothelial deletion of OCT4 exacerbated atherosclerosis in ApoE-null mice plaque stability by regulating endothelial ABCG2 induction to control excessive hemes and ROS [38]. It has been observed that oscillatory shear stress enhances the activity of metalloproteinase (MMP), drives collagen degradation, and weakens fibrous caps, in addition to its role in vascular remodeling with matrix degradation [39][40]. A recent in vivo investigation on coronary arterial plaque clearly demonstrated that the low shear stress area was highly correlated with macrophages, cholesterol crystals, 18F-NaF activity, active microcalcification, and thin-cap fiberoatheroma (TCFA) thinning [41]. Proinflammatory signaling and anerobic metabolism are tightly correlated with atherosclerotic macrophages through the involvement of HIF-1 and PFKFB3. High PFKFB3 expression in mice is linked to an unstable plaque, whereas suppression of PFKFB3 activity stabilizes the plaque [42][43][44][45]. Many recent studies have proven that fluid dynamics and endothelial shear stress are the main pathological factors leading to vulnerable plaques [46].

3.1.2. Plaque Calcification and Endothelium

Intimal calcification is associated with atherosclerosis. Unstable plaques are at risk of rupture due to the involvement of inflammation and microcalcification, which are controlled by wall shear stress [47][48][49][50]. Early proinflammatory and osteogenic cytokines from macrophages including TNF-𝛼, IGF-1, TGF-β, IL-1β, IL-6, and IL-8 induce differentiation of the vascular smooth muscle cells into osteoblast-like cells, initiating microcalcification [51]. TNF-𝛼 induces a reduction in BMPR2, enhancing BMP-9 for osteogenic differentiation in ECs, and induces calcification, thin fibrous cap formation, and plaque rupture [39][40][52][53][54]. Vascular calcification is inhibited by KLF2-mediated suppression of endothelial BMP/SMAD1/5 signaling resulting from laminar flow [55]. The metabolic change from OXPHOS to aerobic glycolysis and downregulation of PPAR-𝜰 resulting from enhanced WNT/β-catenin pathway activation in atherosclerotic lesions increases vascular calcification via lactate secretion. Inhibition of glycolysis by 3-PO, the PFKFB3 inhibitor, reduces EC differentiation and VSMC calcification and enhances cell survival [56][57][58][59]. Recent studies demonstrated that FGF21 reduces vascular calcification and improves vascular function by increasing antioxidant SOD and reducing oxidative stress [60][61].

3.2. Pulmonary Arterial Hypertension (PAH)

The hallmarks of the devastating condition known as pulmonary arterial hypertension (PAH) are neointimal lesions, small vessel constriction, and large vessel stiffness. Pulmonary arterial hypertension occurs when most of the small arteries throughout the lungs narrow in diameter, which leads to increased pulmonary vascular resistance, subsequent right heart failure, and premature death [62]. Endothelial dysfunction is a key factor in the onset and development of artery remodeling and disease progression in pulmonary arterial hypertension (PAH) [63][64][65]. EC dysfunction can be caused by several factors, including inflammatory cytokines, hypoxia, toxins, and external stimuli such as shear stress. Among them, oscillatory shear stress, which leads to disturbed flow, fluid dynamics, and ongoing pathogenic mechanisms, has a substantial impact on PAH patients with neointimal lesion formation, leading to vessel remodeling, which increases pressure in the blood flow [62][66]. PAH begins with a malfunctioning EC, progresses with increased cell proliferation and decreased apoptosis, and finally matures with senescence, which makes PAH difficult to reverse. BMPR2 mutation is frequently found in familial PAH and idiopathic PAH patients. Endothelial BMPR2 controls TGF-β-dependent EndMT, and BMPR2 ligand BMP9 administration has been used to reverse PAH in a rat model. Pulmonary inflammation is believed to put patients with BMPR2 mutations at risk of PAH development [65]. Single-cell RNA sequencing of endothelial cells from a PAH mouse model showed that ECs upregulate genes in the MHC class II pathway, supporting the role of ECs in the inflammatory responses in PAH [67]. A recent report by Chan et al. indicated endothelial senescence is another factor driving PAH [68]. Induction of endothelial senescence was induced by blocking fraxacin (FXN) and mitochondria iron–sulfur (Fe–S) cluster assembly protein, and PAH patients showed reduced fraxacin expression and EC senescence. In addition, senolytic treatment prevented FXN-dependent PAH development in mice. Shyy et al. reported that the transcriptional coactivator MED1 is downregulated in PAH patients and animal models. MDE1 is associated with KLF4, an important transcriptional regulator in endothelial homeostasis, and mediates the expression of BMPR2, ETF, and TGFBR2 [69]. Several studies have demonstrated that disturbed blood flow initiates PAH with EC inflammation, barrier dysfunction, and smooth muscle cell migration through downregulation of eNOS / AKT pathway [70]. Metabolic alterations such as aerobic glycolysis are involved in the development of PAH. Inhibition of the glycolytic enzyme PFKFB3 inhibited PAH progression by reducing vascular remodeling, endothelial inflammation, and leukocyte recruitment [71][72][73]. BMPR2 mediated NOTCH1 activation [74] and increased the nuclear localization of HDAC4 and HDAC5, which are involved in the promotion of EC proliferation and a reduction in apoptosis in PAH ECs [75].

3.3. Sepsis

Sepsis is caused by uncontrolled immune responses to bacterial or viral infections, damaging host tissues. Endothelial proinflammatory phenotype changes are responsible for many sepsis-induced pathological events, including vascular permeability, increased coagulation, and hypoperfusion [76].

3.3.1. Vascular Leakage

Sepsis-induced vascular leakage leads to fluid accumulation and multiorgan failure. A recent study on the ProCESS Trial showed that endothelial permeability markers (sFLT-1, Ang-2, and VEGF) were significantly lower in number in sepsis survivors [77]. Endotoxins or viral pathogens cause vascular leakage via EC junction disassembly or cell death. VE-cadherin is a key adherens junction protein, and its disengagement leads to paracellular permeability. Tyrosine phosphorylation of VE-cadherin induces its intracellular relocalization and loss of cell–cell adhesion. Inflammatory ligands activate Rho-dependent actin stress fiber formation and contractility and paracellular pore formation. Evidence shows that the blockade of endothelial permeability can be a valid strategy for decreasing sepsis mortality [78][79]. Recently, Okada et al. revealed a signaling pathway in ROBO4-dependent endothelial barrier stabilization using small-molecule screening [80]. Endothelial TGF-β-ALK5-Smad2/3 signaling led to ROBO4 expression, whereas BMP9-ALK1-Smad1/5 signaling blocked it, and the ALK1 inhibitor suppressed vascular hyperpermeability and mortality in COVID-19 mouse models. Lactate is known to be a sepsis biomarker, and its newly identified effect on the endothelial barrier has been reported. According to a report by Li et al., lactate disorganizes the VE-cadherin complex via VE-cadherin cleavage and internalization via calpain and Erk2 activation [81].

3.3.2. Thrombosis

Sepsis is often associated with subclinical hypercoagulability or acute disseminated intravascular coagulation (DIC) accompanied by widespread microvascular thrombosis and consumption of platelets and coagulation proteins, leading to bleeding [82]. Sepsis induces a shift in the EC phenotype toward a procoagulant and anti-fibrinolytic status. Activated ECs, in the presence of proinflammatory molecules, express tissue factor (TF), which binds with circulating coagulation factor VII in the extrinsic pathway of the blood coagulation system. Activated ECs promote platelet adhesion and aggregation via the upregulation of various cell surface adhesion molecules [83]. During sepsis, PAI-1(plasminogen activator inhibitor-1) is released by ECs, leading to the inhibition of fibrinolysis and hypercoagulation.

3.3.3. Vascular Tone

Sepsis leads to high cardiac output and decreased peripheral resistance due to vessel dilation and hypotension. Inflammatory ligands cause increased NO synthesis from ECs and smooth muscle cell relaxation [84]. NO also reacts with ROS to form nitrate and nitrate-inducing cytotoxicities [85].
Proinflammatory stimuli such as diabetes, hypercholesterolemia, disturbed flow, ECM remodeling, and inflammatory cytokines induce activation of ECs and modification of phenotypes via the upregulation of inflammatory proteins and activation of several signaling pathways. This proinflammatory phenotype causes EC dysfunction, leading to weakening of the barrier, an increase in permeability, an increase in inflammation, EndoMT, senescence, etc, which is shown in Figure 1. These factors are the main causes of the development of most cardiovascular diseases.
Cells 12 01640 g002 550
Figure 1. EC dysfunction and the progression of vascular diseases.

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