The role of endothelin-1 in vascular remodeling in vivo

Abstract

See article by Dao et al. [4] (pages 61–68) in this issue. Vascular smooth muscle cells (VSMCs) are a major component of the arterial wall and play a critical role in the development of occlusive vascular lesions. In normal vessels, VSMCs are quiescent, differentiated, and contractile and function to maintain vascular tone and blood pressure. In pathological processes such as the response to vascular injury, VSMCs undergo a phenotypic transition whereby they proliferate, migrate from the medial to the intimal layer, and lead to neointimal formation and subsequent vascular remodeling. These resultant vascular changes contribute to the pathological basis of atherosclerosis and restenosis that occur after revascularization procedures such as angioplasty, stenting, and bypass grafting. Endothelin-1 (ET-1) is a potent 21-amino acid vasoconstrictor peptide. ET-1 is mainly generated from the endothelium of blood vessels and functions in a paracrine or autocrine manner on ETA and ETB receptors. These receptors present on VSMCs have been shown to induce contraction and stimulate cell hypertrophy and/or hyperplasia, while endothelial ETB receptors stimulate the production of nitric oxide and prostacyclin and accordingly elicit vasorelaxation. Accumulating evidence indicates that endogenous ET-1 is involved in the vascular remodeling in cardiovascular diseases. For example, local ET-1 production has been shown to be increased in vascular lesions, in neointimal formation after vascular injury, and in atherosclerosis, hypercholesterolemia, and hypertension. Indeed, the administration of ET receptor antagonists reduced the neointimal formation after vascular injury and prevented vascular remodeling in deoxycorticosterone acetate (DOCA)-salt hypertensive rats; this suggested the possibility that ET-1 induces VSMC hyperplasia in this process in vivo. However, several studies using cultured VSMCs showed that ET-1 stimulates VSMC hypertrophy but not hyperplasia in vitro [1–3]. Therefore, it is necessary to develop an understanding of the effect of ET-1 on VSMC hypertrophy and/or hyperplasia in vivo. In the current issue of Cardiovascular Research, Dao et al. [4] have examined the mitogenic or trophic effect of ET-1 in rat small mesenteric arteries in vivo and demonstrated that administration of low doses of ET-1 stimulated protein synthesis (hypertrophy) in the arteries, whereas high doses stimulated both protein and DNA synthesis (hyperplasia).