The Role of Endothelial Cell Injury and Platelet Response in Atherogenesis
Endothelium forms a resistant barrier between flowing blood and vessel wall structures. Endothelial thromboresistance is maintained in part by the synthesis of prostacyclin, a potent prostaglandin inhibitor of platelet function. Loss of endothelial cells, mediated by physical, chemical, infectious or immune mechanisms, exposes the sub endothelium to flowing blood. Platelets react to the subendothelial connective tissue structures, undergoing adhesion and release of intracellular constituents, including a factor that is mitogenic to smooth muscle cells. This growth factor is a heat stable, basic protein (IP 7.4–9.4) of 20,000 Daltons and appears to be responsible for the intimal proliferation of smooth muscle cells that follows endothelial cell desquamation. After a single injury event the intimal lesion regresses over several months. Repeated or continuous endothelial cell loss results in progressive intimal proliferation of smooth muscle cells, their secretion of connective tissue matrix components (collagen, elastin and proteoglycans) and accumulation of lipid when animals are on a hypercholesterolemic diet to form early atherosclerotic intimal lesions. Discontinuance of endothelial injury and restoration of the endothelium appear to be followed by lesion regression except when lipid accumulation is extensive. Possible approaches to atherosclerosis prevention include: 1) protection of the endothelium by interruption or avoidance of endothelial injury factors, and perhaps by pharmacologic protection; 2) inhibition of platelet reactivity; 3) modification of SMC proliferation, secretion or lipid accumulation.