Pathogenes of atherosclerosis.

Causes-:

i) Endothelial injury-: that endothelial injury is the initial triggering event in the development of lesions of atherosclerosis. Actual endothelial denudation is not an essential requirement, but endothelial

dysfunction may initiate the sequence of events. Numerous causes ascribed to endothelial injury in experimental animals

are: mechanical trauma, haemodynamic forces, immunonlogical and chemical mechanisms, metabolic agent as chronic

dyslipidaemia, homocystine, circulating toxins from systemic infections, viruses, hypoxia, radiation, carbon monoxide and

tobacco products.

ii) Intimal smooth muscle cell proliferation-: Endothelial

injury causes adherence, aggregation and platelet release reaction at the site of exposed subendothelial connective

tissue and infiltration by inflammatory cells. Proliferation of intimal smooth muscle cell and production of extracellular

matrix are stimulated by various cytokines such as IL-1 and TNF-α released from invading monocyte-macrophages and

by activated platelets at the site of endothelial injury. These cytokines lead to local synthesis of following growth factors

having distinct roles in plaque evolution:

•)Platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) stimulate proliferation and migration of smooth muscle cells from their usual location in the media into the intima.

•))Transforming growth factor-β (TGF-β) and interferon-(IFN-γ) derived from activated T lymphocytes within lesions

regulate the synthesis of collagen by smooth muscle cells.

•)Smooth muscle cell proliferation is also facilitated by biomolecules such as nitric oxide and endothelin released from

endothelial cells. Intimal proliferation of smooth muscle cells is accompanied by synthesis of matrix proteins—collagen,

elastic fibre proteins and proteoglycans.

iii) Thrombosis-:   As apparent from the foregoing, endothelial injury exposes subendothelial connective tissue resulting in formation of small platelet aggregates at the site and causing proliferation of smooth muscle cells. This causes mild inflammatory reaction which together with foam cells is

incorporated into the atheromatous plaque. The lesions enlarge by attaching fibrin and cells from the blood so that thrombus becomes a part of atheromatous plaque.

iv) Role of dyslipidaemia-: As stated already, chronic  dyslipidaemiain itself may initiate endothelial injury and dysfunction by causing increased permeability. In particular,  hypercholesterolaemia with increased serum concentration of LDL promotes formation of foam cells, while high serum concentration of HDL has anti-atherogenic effect.