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Dichotomous effects of smooth muscle TRPV4 channels on vascular contractility
Author(s) -
Chen YenLin,
Daneva Zdravka,
Sonkusare Swapnil
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.02959
Subject(s) - phenylephrine , vasoconstriction , mesenteric arteries , vascular smooth muscle , vasodilation , medicine , endocrinology , trpv4 , chemistry , contractility , agonist , transient receptor potential channel , blood pressure , constriction , receptor , artery , smooth muscle
Ca 2+ signaling mechanisms in smooth muscle cells (SMCs) determine vascular contractility. Transient receptor potential vanilloid 4 (TRPV4) ion channels have been described as a crucial Ca 2+ influx pathway in SMCs from small, resistance‐sized arteries. However, the impact of SMC TRPV4 (TRPV4 SMC ) channel activity on blood pressure remains unknown, mostly due to the lack of studies in SMC‐specific knockout mice. We hypothesized that TRPV4 SMC channels control the resting blood pressure. Radiotelemetric blood pressure recordings showed reduced daytime and nighttime blood pressures in the inducible, SMC‐specific TRPV4 knockout (TRPV4 SMC ‐/‐ ) mice compared to the control mice. The effect of TRPV4 SMC ‐/‐ on vascular contractility was assessed using two endogenous vasoconstrictor mechanisms‐ 1) SMC α1 adrenergic receptor (α1AR) stimulation and 2) increased intraluminal pressure. Phenylephrine (α1AR agonist)‐induced constriction of pressurized mesenteric arteries (MAs, 80 mm Hg, 1 nM‐10 mM phenylephrine) and blood pressure elevation (10 mg/kg phenylephrine, i.p.) were blunted in TRPV4 SMC ‐/‐ mice, identifying a central role of TRPV4 SMC channels in α1AR‐induced vasoconstriction and blood pressure elevation. Individual Ca 2+ influx signals through TRPV4 SMC channels (TRPV4 SMC sparklets) were recorded using spinning disk confocal imaging in fluo‐4‐loaded MAs pressurized to 80 mm Hg. Phenylephrine (1 mM) activated TRPV4 SMC sparklets, an effect abolished by protein kinase C (PKC) inhibitor (Go6976, 1 mM). These results indicated that PKC‐TRPV4 SMC channel signaling is a major contributor to α1AR‐induced vasoconstriction. In direct contrast with PE‐induced constriction, intraluminal pressure‐induced constriction was higher in MAs from TRPV4 SMC ‐/‐ mice, suggesting that SMC TRPV4 channels limit pressure‐induced vasoconstriction. Previous studies have shown that TRPV4 SMC channels can activate large‐conductance, Ca 2+ ‐sensitive K + (BK) channels, thereby decreasing pressure‐induced vasoconstriction. Consistent with these findings, vasoconstriction in response to BK channel inhibitor (paxilline, 1 mM) was reduced in MAs from TRPV4 SMC ‐/‐ mice, supporting a dilatory TRPV4 SMC channel‐BK channel signaling under resting conditions. In situ proximity ligation assay revealed co‐localization of TRPV4 SMC channels with both α1ARs and BK channels. Overall, TRPV4 SMC channels increase the resting blood pressure but have divergent effects on vascular contractility. TRPV4 SMC channels contribute to α1AR‐induced vasoconstriction but limit pressure‐induced vasoconstriction. Therefore, selective vasoactive stimulus‐TRPV4 SMC channel coupling may determine the impact of TRPV4 SMC channels on vascular resistance.