TRPM4 channels orchestrate pressure-Induced constriction across vascular beds

Resistance arteries and arterioles constrict when intraluminal pressure rises. This intrinsic mechanism, known as the vascular myogenic response, is crucial for regulating blood flow throughout the body. In cerebral arteries, this response requires activation of transient receptor potential melastatin 4 (TRPM4) cation channels in smooth muscle cells (SMCs). Na+ influx through TRPM4 depolarizes the membrane and triggers vasoconstriction. Whether TRPM4 serves a similar role in peripheral resistance arteries is unknown. We hypothesized that TRPM4 is a conserved effector of myogenic tone across multiple vascular beds. To map TRPM4 expression, we generated novel Trpm4-Cre::mTmG reporter mice in which Cre-mediated recombination switches red to green fluorescence in Trpm4-expressing cells. Trpm4-driven GFP was detected in SMCs isolated from cerebral, mesenteric, and skeletal muscle arteries. Using conventional whole-cell and perforated patch-clamp recordings from freshly isolated SMCs, we identified Ca 2+ -activated outwardly rectifying cation currents and stretch-evoked transient inward cation currents that were abolished by the selective TRPM4 blocker 4-chloro-2-(1-naphthyloxyacetamido) benzoic acid (NBA). These TRPM4-like currents were markedly reduced in SMCs from Trpm4fl/fl mice crossed with SM22-Cre (Trpm4-SM22), confirming their molecular identity. In pressure myography experiments, we found that NBA significantly reduced pressure-induced vasoconstriction in cerebral pial arteries (IC50 = 2.7 µM), mesenteric arteries (IC50 = 6.4 µM), and skeletal muscle arteries (IC50 = 8.9 µM) in a concentration-dependent manner. Similarly, myogenic tone was markedly reduced in arteries from all three vascular beds isolated from Trpm4-SM22 mice. Together, these findings identify TRPM4 channels as key regulators of pressure-induced depolarization and constriction in cerebral and peripheral resistance arteries, making them a potential target for modulating regional blood flow in cardiovascular disease. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.