Abstract 16955: Contrasting Effects of Smooth Muscle TRPV4 Channels on Vascular Function

Abstract

Introduction: Transient receptor potential vanilloid 4 (TRPV4) channels are a major Ca 2+ entry pathway in vascular endothelial cells. TRPV4 channels are also expressed in vascular smooth muscle cells (SMC). However, the effect of SMC TRPV4 (TRPV4 SMC ) channels on vascular resistance and blood pressure remains controversial. Hypothesis: We hypothesized that TRPV4 SMC channels are essential regulators of vascular function and blood pressure. Methods: Inducible, SMC-specific TRPV4 knockout (TRPV4 SMC -/- ) mice were used. Blood pressure was monitored using radiotelemetry catheters. SMC Ca 2+ signals were recorded with a spinning disk confocal imaging system. Pressure myography studies assessed vascular reactivity in MAs. Results: Resting diastolic blood pressure and mean arterial pressure were lower in TRPV4 SMC -/- mice when compared to control mice. Selective TRPV4 channel agonist, GSK1016790A (GSK101), induced Ca 2+ influx signals in SMCs that were inhibited by TRPV4 channel inhibitor GSK2193874 and were absent in MAs from TRPV4 SMC -/- mice. In pressure myography studies, GSK101 constricted the MAs in control mice, but not in TRPV4 SMC -/- mice. Moreover, MAs from TRPV4 SMC -/- showed lower vasoconstriction in response to phenylephrine, a α1 adrenergic receptor agonist. These results indicated that Ca 2+ influx through TRPV4 SMC channels contributes to vasoconstriction and increased vascular resistance. However, studies of pressure-induced constriction or myogenic tone indicated that MAs from TRPV4 SMC -/- mice exhibit a higher myogenic constriction at pressures ≥ 60 mm Hg. Moreover, membrane depolarization-induced vasoconstriction (KCl, 33 and 60 mM) was also increased in TRPV4 SMC -/- mice when compared to the control mice, indicating that TRPV4 SMC channels oppose pressure- or membrane depolarization-induced vasoconstriction. Conclusions: TRPV4 SMC channels are essential regulators of resting blood pressure. While TRPV4 SMC channels contribute to α1 adrenergic receptor-induced vasoconstriction, they negatively regulate pressure-induced vasoconstriction. The divergent effects of TRPV4 SMC channels on vascular function may be determined by the selective stimulus-TRPV4 SMC channel coupling and downstream signaling mechanisms.