Novel Smooth Muscle Ca²⁺-Signaling Nanodomains in Blood Pressure Regulation.

Abstract

Ca²⁺ signals in smooth muscle cells (SMCs) contribute to vascular resistance and control blood pressure. Increased vascular resistance in hypertension has been attributed to impaired SMC Ca²⁺ signaling mechanisms. In this regard, transient receptor potential vanilloid 4 (TRPV4_SMC) ion channels are a crucial Ca²⁺ entry pathway in SMCs. However, their role in blood pressure regulation has not been identified. We used SMC-specific TRPV4^-/- (TRPV4_SMC^-/-) mice to assess the role of TRPV4_SMC channels in blood pressure regulation. We determined the contribution of TRPV4_SMC channels to the constrictor effect of α1 adrenergic receptor (α1AR) stimulation and elevated intraluminal pressure: 2 main physiologic stimuli that constrict resistance-sized arteries. The contribution of spatially separated TRPV4_SMC channel subpopulations to elevated blood pressure in hypertension was evaluated in angiotensin II-infused mice and patients with hypertension. We provide first evidence that TRPV4_SMC channel activity elevates resting blood pressure in normal mice. α1AR stimulation activated TRPV4_SMC channels through PKCα (protein kinase Cα) signaling, which contributed significantly to vasoconstriction and blood pressure elevation. Intraluminal pressure-induced TRPV4_SMC channel activity opposed vasoconstriction through activation of Ca²⁺-sensitive K⁺ (BK) channels, indicating functionally opposite pools of TRPV4_SMC channels. Superresolution imaging of SMCs revealed spatially separated α1AR:TRPV4 and TRPV4:BK nanodomains in SMCs. These data suggest that spatially separated α1AR-TRPV4_SMC and intraluminal pressure-TRPV4_SMC-BK channel signaling have opposite effects on blood pressure, with α1AR-TRPV4_SMC signaling dominating under resting conditions. Furthermore, in patients with hypertension and a mouse model of hypertension, constrictor α1AR-PKCα-TRPV4 signaling was upregulated, whereas dilator pressure-TRPV4-BK channel signaling was disrupted, thereby increasing vasoconstriction and elevating blood pressure. Our data identify novel smooth muscle Ca²⁺-signaling nanodomains that regulate blood pressure and demonstrate their impairment in hypertension.