TRPM4 Couples Mechanical Force to Myogenic Constriction Throughout the Resistance Vasculature.

BACKGROUND: Myogenic tone is a fundamental property of resistance arteries that stabilizes tissue perfusion by coupling intraluminal pressure to smooth muscle cell (SMC) depolarization, Ca2+ influx, and vasoconstriction. TRPM4 (transient receptor potential melastatin 4) cation channels are required for this response in cerebral arteries, but whether TRPM4-dependent mechanotransduction is conserved across the broader resistance vasculature has remained unknown.

METHODS: We combined droplet digital PCR, a newly generated Trpm4-Cre transgenic reporter mouse line, native-cell patch-clamp electrophysiology, pressure myography, selective pharmacological inhibition, and novel SMC-specific Trpm4-knockout (Trpm4-smKO) mice to define the expression, regulation, and functional importance of TRPM4 in cerebral, mesenteric, and skeletal muscle resistance arteries.

RESULTS: Trpm4 transcripts were detected in all three vascular beds, and genetic reporter-based mapping localized TRPM4 expression to SMCs in multiple organs. Using conventional whole-cell patch-clamp electrophysiology, we recorded cation currents activated by high intracellular [Ca2+] and sensitive to the selective TRPM4 blocker 4-chloro-2-(1-naphthyloxyacetamido) benzoic acid (NBA) in native SMCs from all three beds. In cells patch-clamped using the amphotericin B-perforated configuration, stretching the plasma membrane by applying negative pressure (-20 mmHg) through the patch pipette activated transient inward cation currents that were suppressed by NBA. The selective angiotensin II type 1 receptor (AT1R) blocker losartan also inhibited stretch-induced currents without affecting Ca2+-activated whole-cell TRPM4 currents, indicating that AT1R signaling is required for mechanotransduction in SMCs from all three vascular beds. In pressurized arteries with established myogenic tone, NBA produced reversible, concentration-dependent suppression of pressure-induced constriction of cerebral, mesenteric, and skeletal muscle arteries while sparing constriction induced by direct depolarization of SMCs with high (60 mM) extracellular [K+]. TRPM4-dependent whole-cell currents and stretch-induced cation currents were decreased in SMCs from Trpm4-smKO mice, and myogenic tone was essentially absent in all three vascular beds from these animals.

CONCLUSIONS: These findings show that TRPM4 is essential for pressure-induced SMC depolarization and myogenic constriction in the resistance vasculature.