Urotensin-II promotes vascular smooth muscle cell proliferation through store-operated calcium entry and EGFR transactivation

Abstract

Our data show for the first time that UII-induced VSMCs proliferation and CREB activation requires a complex signalling pathway that involves on the one hand SOCE mediated by STIM1, Orai1, and TRPC1, and on the other hand EGFR, ERK, and CaMK activation.

Orai channel-mediated Ca2+ signals in vascular and airway smooth muscle

“…The latter are likely activated secondarily to store depletion and Ca 2ϩ entry through Orai1 channels (e.g., direct activation by Ca 2ϩ or Ca 2ϩ -dependent delivery to the PM of TRPC-containing vesicles) (11,12,17,91). Consistent with this notion, coimmunoprecipitation experiments showed that urotensin II enhanced the STIM1-Orai1 and Orai1-TRPC1 interactions in cultured aortic SMCs (73). Rodriguez-Moyano et al (73) also showed that pharmacological inhibition of SOCE (by 50 M 2-APB or 10 M ML-9) significantly inhibited epidermal growth factor receptor and ERK phosphorylation in response to urotensin II.…”

“…Consistent with this notion, coimmunoprecipitation experiments showed that urotensin II enhanced the STIM1-Orai1 and Orai1-TRPC1 interactions in cultured aortic SMCs (73). Rodriguez-Moyano et al (73) also showed that pharmacological inhibition of SOCE (by 50 M 2-APB or 10 M ML-9) significantly inhibited epidermal growth factor receptor and ERK phosphorylation in response to urotensin II. Reciprocally, pharmacological inhibition of epidermal growth factor receptor and ERK inhibited the Ca 2ϩ increase and proliferation of cultured aortic SMCs in response to urotensin II.…”

“…The vasoactive agonist urotensin II, which also promotes vascular SMC proliferation, enhanced Ca 2ϩ influx through a pathway pharmacologically reminiscent of SOCE in vascular SMCs (18,73). Under conditions where cytosolic Ca 2ϩ was buffered to 150 nM by high concentrations of a Ca 2ϩ chelator (10 mM BAPTA-5 mM CaCl 2 ), urotensin II activated whole cell currents in cultured aortic SMCs that were biophysically and pharmacologically reminiscent of I CRAC , including inward rectification and inhibition by 5 M Gd 3ϩ (73).…”

“…Under conditions where cytosolic Ca 2ϩ was buffered to 150 nM by high concentrations of a Ca 2ϩ chelator (10 mM BAPTA-5 mM CaCl 2 ), urotensin II activated whole cell currents in cultured aortic SMCs that were biophysically and pharmacologically reminiscent of I CRAC , including inward rectification and inhibition by 5 M Gd 3ϩ (73). Interestingly, urotensin II-mediated Ca 2ϩ entry measured with fura 2 in these cultured aortic SMCs was dependent on TRPC1, in addition to STIM1 and Orai1 (73). This likely reflects close interactions between STIM1/Orai1-mediated I CRAC and nonselective TRPC channels.…”

“…Reciprocally, pharmacological inhibition of epidermal growth factor receptor and ERK inhibited the Ca 2ϩ increase and proliferation of cultured aortic SMCs in response to urotensin II. Pharmacological inhibition of SOCE or knockdown of STIM1, Orai1, or TRPC1 inhibited urotensin II-mediated activation of the transcription factor cAMP response element-binding protein (CREB), suggesting a role for vascular SMC Ca 2ϩ signaling in CREB activation and cell proliferation (73).…”