Non-genomic activation of smooth muscle TRPV4 channels by mineralocorticoid receptors regulates vasoconstriction

The mineralocorticoid receptor (MR) is known to regulate vascular tone and fluid balance through its well-characterized genomic signaling pathways. Interestingly, aldosterone, an MR agonist, was shown to rapidly elevate cytosolic calcium levels in vascular smooth muscle cells (SMCs), suggesting a non-genomic mechanism. However, the specific calcium channel mediating this effect remains unidentified. Transient receptor potential vanilloid 4 (TRPV4) channels represent a critical pathway for calcium influx in SMCs, directly impacting vascular constriction and blood pressure regulation. We hypothesized that MR signaling increases the activity of TRPV4 channels in SMCs through non-genomic mechanisms. Patch-clamp recordings in freshly isolated SMCs from small mesenteric arteries of male and female C57Bl/6 mice showed that aldosterone increases TRPV4 currents within seconds. This effect was abolished in SMC-specific MR or TRPV4 knockout (KO) mice, identifying a TRPV4 channels as a calcium influx pathway activated by non-genomic MR signaling. Importantly, aldosterone-mediated TRPV4 activation was also observed in human skeletal muscle arteries, highlighting the clinical relevance of non-genomic MR–TRPV4 signaling. Functional studies using pressure myography revealed that MR signaling promotes mesenteric artery constriction, and this effect is attenuated by TRPV4 inhibition. Moreover, single-molecule localization microscopy with total internal reflection fluorescence (TIRF) and proximity ligation assays showed that MR colocalizes with TRPV4 channels at the SMC plasma membrane. MR:TRPV4 colocalization and aldosterone-activation of TRPV4 channels were reduced in SMCs from SMC-specific Cav1 KO mice, suggesting that Cav1 scaffolds MR–TRPV4 signaling. Together, these findings uncover a novel non-genomic MR signaling mechanism, whereby Cav1-scaffolded MR–TRPV4 microdomains promote vasoconstriction, offering new insights into MR-driven mechanisms underlying vasoconstriction and blood pressure regulation. Funding sources: R01HL142808, R01HL146914, R01HL167208, R01EY034238. 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.