ABSTRACT
Figure 2.1 Schematic presentation of the cellular and molecular mechanisms of atherosclerosis that lead to the formation of plaques in the vessel wall and to arterial stenosis. The endothelium plays a key role in vascular homeostasis through the release of a variety of autocrine and paracrine substances.6 A healthy endothelium is also anti-atherogenic because of effects that
encompass inhibition of platelet aggregation, smooth muscle cell (SMC) proliferation and leukocyte adhesion. It is well established that nitric oxide (NO) is a crucial factor for the health and function of endothelial cells (ECs) due to its significant vasoprotective and cardioprotective effects, including inhibition of both platelet aggregation and inflammatory cell adhesion to ECs, disruption of proinflammatory cytokine – induced signalling pathways, inhibition of apoptosis, and regulation of tissue energy metabolism.7 During endothelial dysfunction, there is a reduced bio-availability of NO, causing the impairment of endothelium-dependent vasodila-tion and abnormalities in endothelial interactions with blood-borne cells such as leukocytes and platelets. In the dysregulated endothe-lium, intracellular granules like Wiebel-Palade bodies (storing von Willebrand-vWf and P-selectin) fuse with the cell membrane and consequently expose vWf and P-selectin on the endothelium surface. These factors can promote tethering and rolling of blood platelets at the vascular injury site via interaction with integrin GPIb/IX/V and P-selectin glycoprotein ligand-1 (PSGL-1), respectively, present on the platelet surface.8 The P-selectin and other selectins (e.g., E-and L-) also mediate adhesion of inflammatory cells like leukocytes at the injury site. There is also an increased permeability of endothe-lium to low density lipoprotein (LDL) particles that enter the sub-endothelium. Within the arterial wall, these LDL particles undergo oxidation and endocytosis by the macrophages (via scavenger re-ceptors pathways), leading to intracellular cholesterol accumulation and the formation of “foam” cells.8 The final outcome of this complex process is the development of atherosclerotic plaques that consist of lipid-rich necrotic cores made of foam cells and fibrous collagenous cap. The cap is formed by Extracellular Matrix (ECM) degradation and remodelling-processes mediated by macrophage and smooth muscle cell activity.9These dynamic interactions between the immune system, the endothelial barrier, and the lipoproteins form the mechanistic basis for our current understanding of atherosclerotic disease. Hence, the specific roles of all the cellular and molecular players in this dynamic interplay of atherogenesis still remain unknown. Over time, mature lesions accumulate and form atherosclerotic plaques which may manifest clinically due to plaque related complications. Expansion of atherosclerotic lesions may lead to gradual stenosis of the lumen and, eventually, occlusion of the vessel initiating the clinical symptoms of angina and heart attack.
