Vascular injury and thrombosis are common initial events in atherosclerosis (reviewed in ref. 28). Intrinsic pathway enhances the thrombo-genicity of atherosclerotic lesions after the removal of the endothelial layer and exposure of smooth muscle cells (SMCs) and macrophages to blood flow (29). Studies on plasma levels of tissue factor pathway inhibitor (TFPI) in patients with various diseases suggest that TFPI (a Kunitz-type protease inhibitor that inhibits the initial reactions of blood coagulation) may be a marker of EC dysfunction (30). Patients suffering from proven peripheral artery disease (PAD) have higher plasma levels of tissue factor (TF) and vascular endothelial growth factor (VEGF) compared with controls, with a significant correlation between the two. This suggests a link between the hypercoagulable state in PAD and the process of angiogenesis (31).
Plasminogen activator inhibitor (PAI)-1 plasma levels depend on gene regulation, insulin resistance, diabetes mellitus (DM), hypertriglyceridemia, and activated renin angiotensin system through a receptor-dependent mechanism (reviewed in ref. 32). In Apo E -/- PAI-1 -/mice, loss of PAI-1 promoted the growth of advanced atherosclerotic plaques as a result of enhanced ECM deposition. Also, plaques exhibited collagen fiber disorganization and degradation; therefore, though PAI-1 may promote plaque growth caused by its antifibrinolytic properties, PAI-1 has a protective role by limiting plaque growth and preventing abnormal matrix remodeling (33).
Annexin (AN) II is a coreceptor on ECs for plasminogen and tissue plasminogen activator (tPA). Recombinant AN II enhanced plasmin generation on HUVECs in vitro, reduced thrombus formation in a rat carotid artery thrombus model (34), and increased urokinase plasminogen activator (uPA) expression in atherosclerotic arteries contribute to intimal growth and constrictive remodeling leading to lumen loss (although increased uPA expression in EC decreases intravascular thrombosis) (35).
Tissue transglutaminase (tTG), a family of enzymes catalyzing the formation of stable covalent crosslinks between proteins, are upregu-lated by thrombin in HUVEC and have a role in the stabilization of atherosclerotic plaques (36).
In a cross-sectional study, the presence and extent of atherosclerosis, as measured by ultrasound, correlated positively with plasma fibrinogen (37). Plasma fibrin D-dimer levels are strongly and independently associated with the presence of CAD in patients with stable angina (38). However, there is doubt about its etiologic contribution because elevated plasma fibrinogen concentrations in Apo E*3-Leiden transgenic mice do not affect the progression of diet-induced atherosclerotic lesions (39). y A/y fibrinogen is a fibrinogen isoform that constitute 15% of total plasma fibrinogen. It contains an additional binding site for factor XIII and active thrombin, and forms fibrin clots that are resistant to fibrinolysis in vitro. This isoform is not associated with age or gender, and was higher in CAD patients than controls independent of total fibrinogen levels (which rises with age and are higher in women) (40).
Mast cell (MC), the high basal cardiac and serum histamine in Apo E k/o mice, along with the high number of cardiac mast cells, suggest possible ongoing cardiac mast cell activation that may participate in atherosclerosis (41).
Activated MCs may participate in the weakening and rupture of atherosclerotic plaques by causing the loss of matrix-synthesizing SMC by inhibiting the proliferation of SMCs in vitro and reducing their ability to produce collagen. Chymase, a neutral serine protease secreted by activated mast cells, can also inhibit SMC-mediated collagen synthesis, and moreover cause degradation of the collagen matrix by activating latent interstitial collagenase (matrix metalloproteinase [MMP]-1). Furthermore, chymase can induce SMC apoptosis (reviewed in ref. 42).
MC chymases also degrade Apo E and apo angiotensin II (All) and inhibit the apoprotein-mediated removal of macrophage cholesterol in Apo A1 knockout (KO) mice (43). Chymase and angiotensin converting enzyme (ACE) regulate All production in distinct tissue compartments (44).
Platelets produce NO, which is increased by the dietary supplementation of L-arginine to hypercholesterolemic rabbits. This effect is associated with reduced platelet aggregation (45). Platelet activation is increased in patients with CAD (46). Hypercholesterolemia primes human platelets for recruitment to lesion-prone sites via endothelial von Willebrand factor (vWF), platelet GPlba, and platelet p-selectin before lesions are detectable (47).
Platelet factor 4 (PF4), a cationic protein released by activated platelets, inhibits the catabolism of LDL. Retention of LDL complexes on cell surfaces may facilitate pro-atherogenic modification (48), such as promoting oxidized oxLDL formation, binding to oxLDL directly, increasing oxLDL binding to vascular cells and macrophages, and increasing the amount of oxLDL esterified by macrophages (49).
Activated platelets stimulate MCP-1 and intercellular adhesion molecule (ICAM)-1 of HUVECs (50). Circulating activated platelets bind to leukocytes, preferentially monocytes, to form platelet-monocyte/leuko-cyte aggregates that interact with atherosclerotic lesions leading to the delivery of the platelet-derived chemokines and platelet factor 4 (CXCL4) to the monocyte surface and endothelium of atherosclerotic arteries (51).
Receptors for extracellular nucleotides, the P2 receptors, have been recognized as fundamental modulators of leukocytes, platelets, SMCs and EC, P2 receptors mediate chemotaxis, cytokine secretion, NO generation, platelet aggregation, and cell proliferation in response to accumulation of nucleotides into the extracellular milieu. Clinical trials have shown the benefit of antagonists of the adenosine diphosphate (ADP) platelet receptor(s) in the prevention of vascular accidents in patients with atherosclerosis (reviewed in ref. 52).
Activated macrophages stimulate angiogenesis that can further recruit inflammatory cells and more angiogenesis. Plaque angiogenesis promotes the growth of atheromas and the angiogenesis inhibitor, angiostatin, reduces plaque angiogenesis and inhibits atherosclerosis (53).
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