Deformation-induced endothelin B receptor-mediated smooth muscle cell apoptosis is matrix-dependent

Abstract

To maintain normal blood flow, pressure overload in both arteries andveinsrequiresastructuraladaptation ofthevessel wall (remodelling) that involves smooth muscle cell (SMC) hypertrophy and/or hyperplasia. Due to its potent vasoconstrictor and growth-promoting effects, endothelin-1 (ET-1) is a likely candidate to initiate and/or promote remodelling in blood vessels exposed to a chronic increase in blood pressure. To test this hypothesis, isolated segments of the rabbit carotid artery and jugular vein were perfused at different levels of intraluminal pressure. In both types of segments, pressure overload (160 and 20 mmHg, respectively) resulted in an increase in endothelial prepro-ET-1 and SMC endothelin B receptor (ET B -R) expression. Moreover, in pressurised segments from the carotid artery an ET B -R antagonistsensitive increase in SMC apoptosis in the media was observed, while in the vein medial SMC started to proliferate. Isolated SMC from these rabbit blood vessels as well as from the aorta and vena cava of the rat, when cultured on a collagen or laminin matrix, uniformly revealed an ET B -R-mediated increase in apoptosis upon exposure to mechanical deformation plus exogenous ET-1 (10 nmol/L). However, when grown on a fibronectin matrix, the cultured SMC did not respond with an increase in apoptosis under otherwise identical experimental conditions. These findings suggest that deformationinduced activation of the endothelin system in the vessel wall not only plays a crucial role in remodelling, but that the structural components of the vessel wall, in particular the cellmatrix interaction, determine how SMC respond phenotypically to these changes in gene expression.

Signalling and regulation of collagen I synthesis by ET‐1 and TGF‐β1

“…A changed ratio of ET‐receptor subtypes results in a modified signal transduction, because ETA‐ and ETB‐receptors couple in part to different Gα proteins. For example in smooth muscle cells, a shift towards the ETB‐receptor causes a deformation of these cells [60], whereas in human myocardial fibroblasts a shift towards the ETA‐receptor profoundly interferes with cellular Ca 2+ regulation [57]. Moreover, it is described that the ETA‐receptor regulates proliferation by pro‐ and antimitogenic actions [24,61].…”

Different role of endothelin ETA and ETB receptors and endothelial modulators in diabetes-induced hyperreactivity of the rabbit carotid artery to endothelin-1

“…Because endothelin ET B activation mediates opposite effects depending of the endothelial or muscular location of the receptor, the sum of these effects could have masked the effect of the activation of each of them individually. However, other studies describe the presence of endothelin ET B receptors functionally active in the rabbit carotid artery, and their possible role in several pathophysiological conditions (Lauth et al, 2000;Cattaruzza et al, 2002). In vivo studies have demonstrated that endothelin-1 contributes to regulation of the vascular tone of human resistance vessels by stimulating NO activity, and this effect is mediated through endothelial endothelin ET B receptors (Cardillo et al, 2000).…”

Biomechanical Stress-induced Signaling in Smooth Muscle Cells: An Update

“…It is known that the mechanical stress results in an increase of endothelin receptor expression in VSMCs and that exposure of these cells to endothelin will induce apoptosis via an endothelin receptor dependent mechanism [217,218]. This mechanism is sensitive to ECM interactions as it is observed in intact vessels in VSMCs cultured on fibronectin coated plates [217].…”