Smooth Muscle TRPV4 Channels Signaling Nanodomains in Blood Pressure Regulation

Abstract

Transient receptor potential vanilloid 4 (TRPV4) channel is a crucial Ca2+influx pathway in arterial smooth muscle cells (SMCs). However, the effect of SMC TRPV4 (TRPV4SMC) channel activity on resting blood pressure has not been investigated. We hypothesized that SMC TRPV4 (TRPV4SMC) channels regulate blood pressure under homeostatic and hypertensive conditions. Radiotelemetric recordings showed lower resting blood pressure in SMC‐specific TRPV4‐/‐ (TRPV4SMC‐/‐) mice than control mice, suggesting that TRPV4SMC channels elevate the resting blood pressure. α1 adrenergic receptor (α1AR) stimulation–induced constriction was blunted in small mesenteric arteries (MAs) from TRPV4SMC‐/‐ mice, whereas intraluminal pressure–induced (myogenic) constriction was increased. Moreover, both α1AR stimulation and increased intraluminal pressure activated elementary Ca2+ influx signals through TRPV4SMC channels (TRPV4SMC sparklets) in MAs from control mice. These data supported the concept that TRPV4SMC channels contribute to α1AR–induced vasoconstriction but oppose myogenic vasoconstriction. Inhibition of Ca2+‐sensitive K+ (BK) channels abolished the effect of TRPV4SMC channels on myogenic vasoconstriction, indicating a crucial role for TRPV4SMC–BK channel signaling in limiting myogenic vasoconstriction. Accordingly, a direct activation of TRPV4SMC channels with GSK1016790A (30 nM) increased BK channel currents in SMC patch‐clamp experiments. α1AR stimulation, however, was unable to increase BK channel currents, implying two functionally opposite pools of TRPV4SMC channels. Direct STORM superresolution imaging revealed a1AR:TRPV4SMC and TRPV4SMC:BK channel co‐localization, and almost no co‐localization of a1ARs and BK channels. Together, these data supported the idea of spatially separated and functionally opposite nanodomains of TRPV4SMC channels. We further hypothesized that an imbalance between these two nanodomains contributes to elevated blood pressure in hypertension. In skeletal muscle arteries from hypertensive patients, a1AR activation of TRPV4SMC channel currents was accentuated whereas TRPV4SMC activation of BK channel currents was impaired. Similarly, MAs from angiotensin II‐infused hypertensive mice showed increased activity of constrictor a1AR–TRPV4SMC signaling and impairment of dilatory TRPV4SMC–BK channel signaling. Collectively, our data identify novel smooth muscle Ca2+ signaling nanodomains that regulate blood pressure and demonstrate their impairment in hypertension.