Effects of endothelin-1 on vascular smooth muscle cell phenotypic differentiation.
Endothelin-1 (ET-1) produced by vascular endothelial cells has been proposed to act in a paracrine manner on adjacent smooth muscle cells (SMCs) in vivo, exerting a variety of short- and long-term effects. Although some of the in vitro ET-1-mediated effects are related to growth-promoting events, the physiological significance of these observations remains to be clarified. Reported discrepancies of the mitogenic potential of ET-1 may relate to differences in culturing conditions (submitogenic levels of serum in combination with ET-1). Because ET-1 has been implicated in proliferation of vascular SMCs (VSMCs) at sites of vascular injury, as well as pathological events during atherogenesis, a clarification of the mitogenic effects of ET-1 is important. This study demonstrates the possible autocrine role for ET-1 in the regulation of the vasculature, its influence on VSMC cell cycle, and autocrine and phenotypic regulation of VSMCs. Stimulation of quiescent VSMCs with a variety of peptides resulted in the secretion of biologically active ET-1 by VSMCs. In contrast to previous reports, long-term exposure (12-15 days) of VSMCs to ET-1 in nonmitogenic medium did not promote cycling of cells. On the contrary, ET-1 attenuated the cycling of VSMCs in the S and G2/M phases and interrupted progression through the cell cycle at late G1/early S phase. Subsequent to ET-1 exposure, VSMCs expressed increased levels of smooth muscle-specific alpha-actin. Therefore, autocrine-produced ET-1 may contribute to phenotypic differentiation of VSMCs.
D000199:Actins / Q000096:biosynthesis; D000818:Animals; D015152:Blotting, Northern; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D016232:Endothelins / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011233:Precipitin Tests; D051381:Rats; D016212:Transforming Growth Factor beta / Q000378:metabolism
D000199:Actins; D016232:Endothelins; D010982:Platelet-Derived Growth Factor; D016212:Transforming Growth Factor beta; C075278:platelet-derived growth factor A