The formation and progression of
atherosclerotic plaques followed by
rupture,
thrombus formation and vessel blockage leads to ischemic tissue damage and the clinical condition underlying most
cardiovascular disease. Therapeutic agents for the prevention of
atherosclerosis have all targeted epidemiologically-identified and relatively easily measured risk factors (e.g.
lipids and blood pressure). This strategy has proven somewhat effective but is of less than optimal efficacy as rates of
cardiovascular disease remain high. Treatment targeting the mechanisms of
atherosclerosis in the vessel wall is a conceptually attractive proposition to
complement the risk factor directed strategy. Vascular smooth muscle cells (VSMC) are the major cellular component of the vascular media and migration and proliferation leads to the formation of the
neointima the development of which renders the vessels particularly sensitive to
atherosclerosis. Numerous
hormones and
growth factors act on VSMC to cause migration, proliferation and the secretion of extracellular matrix and modulation or dysfunction of these processes is the most likely cause of
atherosclerosis.
Endothelin-1 (ET-1) is a 21
amino acid peptide that acts on 7 transmembrane
G protein coupled receptors to elicit a plethora of responses that can modulate the behaviour of VSMCs and thus impact on the development of
atherosclerosis. ET-1 is elevated in
atherosclerotic plaques. People with diabetes have accelerated
atherosclerosis and also show elevated plasma levels of ET-1. This review addresses the actions of ET-1 on VSMC and the signalling pathways through which it mediates its effects as the latter represent potential therapeutic targets for the prevention of
atherosclerosis.