Shared Mechanotransduction Pathways in Retinal and Cerebral Arterial Smooth Muscle Cells

The retinal vasculature is frequently used as a surrogate for the cerebral microcirculation; however, whether fundamental vascular control mechanisms are shared between the two beds remains unknown. Here, we compared signaling pathways underlying the myogenic response, a key autoregulatory mechanism that causes muscularized arteries and arterioles to constrict when intraluminal pressure rises. Prior work from our laboratory demonstrated that transient receptor potential melastatin 4 (TRPM4), a Ca 2+ -activated, monovalent selective cation channel, is essential for pressure-induced constriction of cerebral arteries and that TRPM4 in smooth muscle cells (SMCs) is activated downstream of a force-sensitive signaling cascade initiated by Gq-protein-coupled angiotensin II type 1 receptors (AT1Rs). Membrane stretch activates AT1Rs in a ligand-independent manner, stimulating phospholipase C, generating inositol 1,4,5-trisphosphate (IP3), and evoking IP3 receptor (IP3R)-mediated Ca 2+ release from the sarcoplasmic reticulum. The resulting Ca 2+ signals activate Na+ influx through TRPM4, thereby depolarizing the SMC membrane and promoting constriction. Here, we asked whether a similar pathway operates in retinal artery SMCs. Trpm4, Itpr1, and Itpr2 (encoding IP3R1 and IP3R2, respectively) expression was detected in retinal arteries by PCR. To identify TRPM4-expressing cells in situ, we generated a novel Trpm4-Cre::mTmG reporter mouse in which Cre-mediated recombination switches red to green fluorescence in Trpm4-expressing cells. SMCs in retinal arteries from these mice were green, confirming Trpm4 expression. TRPM4 activity was recorded in freshly isolated retinal artery SMCs using perforated patch-clamp electrophysiology. Applying negative pressure (−20 mmHg) to the patch pipette to stretch the plasma membrane at a holding potential of −70 mV evoked transient inward cation currents (TICCs) that were abolished by the selective TRPM4 blocker 4-chloro-2-(1-naphthyloxyacetamido) benzoic acid (NBA). Stretch-induced currents were significantly decreased by losartan, a selective AT1R antagonist, and application of angiotensin II in the absence of negative pressure increased TICC activity. Xestospongin C, a selective IP3R inhibitor, also markedly decreased stretch-induced TRPM4 currents. These data indicate that stretch-induced activation of AT1Rs stimulates IP3R-dependent TRPM4 currents in retinal artery SMCs, demonstrating that mechanotransduction pathways engaged by intraluminal pressure are conserved between retinal and cerebral arteries, supporting the use of the retinal vasculature as a model for cerebrovascular function. This work was supported by the National Institutes of Health Grant R35HL155008 (to S. Earley) 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.