Key result
In human pulmonary artery smooth-muscle cells, endothelin-1 acts as an autocrine factor promoting serum-induced proliferation, which is reduced by ET-A receptor antagonists and PH drugs.
Endothelin-1 released from human pulmonary artery smooth muscle cells promotes cellular proliferation in an autocrine manner, which can be inhibited by drugs used for pulmonary hypertension.
No immediate clinical implications for PH; extends in vitro mechanistic data on ET-A blockade.
Endothelin (ET)-1 is a potent vasoconstrictor and comitogen/ proliferation factor for vascular smooth muscle (VSM). As such, it has been implicated in the vascular wall remodeling observed in pulmonary hypertension (PH). Although the endothelium is considered the main source of ET-1, it can be released by other cells including VSM and may mediate proliferation in an autocrine manner. We investigated this possibility using human pulmonary artery smooth-muscle (HPASM) cells. Serum stimulated the release of ET-1 from HPASM cells in a concentration-dependent fashion and caused proliferation as determined by [(3)H]thymidine uptake and increase in cell number. Addition of an ET-A receptor antagonist (BQ123) or an inhibitor of ET-1 synthesis (phosphoramidon) reduced the proliferation induced by serum, confirming an autocrine role for ET-1. In addition, treatment of HPASM cells with two drug types used in the management of PH-cicaprost, a stable prostacyclin-mimetic; or diltiazem, a calcium-channel blocker-reduced ET-1 release from these cells. We conclude that ET-1 released from HPASM cells has an autocrine function in serum-induced proliferation, with important implications for the pathogenesis of human vascular remodeling. Drugs used in the treatment of PH may act, at least in part, by inhibiting this autocrine loop.
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Wort et al. (2001) studied Pulmonary hypertension. ET-A receptor antagonist (BQ123), phosphoramidon, cicaprost, or diltiazem vs. Serum stimulation without inhibitors was evaluated on Cellular proliferation ([(3)H]thymidine uptake and increase in cell number) and ET-1 release. In human pulmonary artery smooth-muscle cells, endothelin-1 acts as an autocrine factor promoting serum-induced proliferation, which is reduced by ET-A receptor antagonists and PH drugs.
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