Regulation of endothelin-1 synthesis in human pulmonary arterial smooth muscle cells effects of transforming growth factor-β and hypoxia

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Abstract
Objective : Endothelin-1 (ET-1) potently regulates pulmonary vascular tone and promotes vascular smooth muscle cell growth. Clinical and animal studies implicate increased ET-1 production in the pathogenesis of primary and secondary pulmonary hypertension. Although pulmonary arterial smooth muscle cells (PASMCs) synthesize ET-1 under basal conditions, it is unknown whether factors that may be important in pulmonary hypertension, such as transforming growth factor-β (TGF-β) or hypoxia, augment ET-1 production by these cells. Methods : We determined the effect of TGF-β and hypoxia on ET-1 release and preproET-1 mRNA from cultured rat and human PASMCs. Results : In the basal state, rat and human PASMCs synthesize, on average (mean±S.E.M.), 872±114 and 563±57 pg ET-1/mg cell protein over 24 h, respectively, a level that causes autocrine and paracrine effects in other tissues. TGF-β significantly increases the expression of preproET-1 mRNA and ET-1 production by both rat and human PASMCs. Hypoxia for 24 h, however, does not affect ET-1 release from rat or human PASMCs. Conclusions : Cultured rat and human PASMCs are a source of ET-1 production. Enhanced ET-1 release from PASMCs may contribute to the pathophysiology of TGF-β-induced pulmonary hypertension. ET-1 production by PASMCs is unlikely to contribute to the role of ET-1 in hypoxia-induced pulmonary vasoconstriction.

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