Involvement of TRPM4 in Pressure and Agonist‐Induced Vasoconstriction in the Cerebral Microcirculation

Abstract

Cerebral parenchymal arterioles (PAs) play a critical role in regulating blood flow and perfusion pressure in the brain. These arterioles are centrally involved in neurovascular coupling and are substantially more sensitive to mechanical and chemical stimulants compared to cerebral arteries on the surface of the brain, i.e. the pial arteries. Intravascular pressure, an essential vasomotor stimulant, causes membrane depolarization and vasoconstriction (myogenic tone). Previous research and recent published work from our laboratory indicates the involvement of a transient receptor potential channel (TRPM4) and purinergic receptors (P2Y4 and P2Y6) in myogenic tone development of pial arteries and PAs, respectively. In the current study, the relationship between TRPM4 and P2Y receptors, and their contribution to myogenic tone development in PAs were investigated. Here we report that TRPM4 mRNA signal is present in PAs. In functional (pressure myography) studies, the selective TRPM4 channel blocker 9‐phenanthrol substantially inhibited myogenic tone of endothelium‐denuded PAs with an IC50 of 28 μM. Suppression of TRPM4 expression using siRNA constructs significantly reduced myogenic constriction; PAs treated with control siRNA and TRPM4 siRNA developed 45% ± 2% and 33% ± 4% myogenic tone, respectively. Moreover, in denuded PAs, 9‐phenanthrol (30 μM) attenuated P2Y4 (UTPγS, 0.5 μM) and P2Y6 (MRS2693, 1 μM) agonist‐induced vasoconstriction by 67% and 68%, respectively. Consistent with this finding, TRPM4 ion channel activity in myocytes isolated from PAs was significantly elevated by UTPγS (0.5 μM). These results indicate that TRPM4 contributes to pressure‐induced, purinergic receptor‐mediated vasoconstriction of PAs.