Regulation of endothelin-1 production in cultured rat vascular smooth muscle cells

Endothelin-1 (ET-1) is secreted from all rat vascular smooth muscle cells ( VSMCs) examined, in addition to endothelial cells (ECs). An average secreti on rate of ET-1 from rat VSMCs was determined to be 10% that excreted from ECs. We examined the effects of 22 substances on ET-1 secretion from VSMCs and compared them with those from ECs. Transforming growth factor-beta (1) (TGF-beta), acidic and basic fibroblast growth factors, epidermal growth fa ctor, angiotensin II, and adrenaline stimulated ET-1 secretion from VSMCs, whereas forskolin, thrombin, and platelet-derived growth factor-BE reduced it. Only TGF-beta and phorbol ester elicited consistent effects on ET-1 sec retion from VSMCs and ECs. Regulation of ET-1 and adrenomedullin secretion from VSMCs was distinctly different. These data suggest that ET-1 productio n in VSMCs is regulated by a mechanism separate from that in ECs and from a drenomedullin production in VSMCs. Chromatographic analysis showed immunore active ET-1 secreted from VSMCs was mainly composed of big ET-1. whereas ap proximately 908 of that from ECs was ET-1. By TGF-beta stimulation of VSMCs , the ratio of big ET-1 to ET-1 was further increased. Because big ET-1 is converted into ET-1 only on the surface of the ECs in the culture system, b ig ET-1 secreted from the VSMCs may function as a mediator transmitting a s ignal from VSMCs to ECs in vivo.