Central Role of TRPM4 Channels in Cerebral Blood Flow Regulation

Abstract

BACKGROUND AND PURPOSE: The transient receptor potential channel TRPM4 is critically linked to the myogenic constrictor response of cerebral arteries that occurs when intravascular pressure increases. This myogenic behavior is thought to be fundamentally involved in the mechanisms of blood flow autoregulation. In this study, we tested the hypothesis that TRPM4 channels in cerebrovascular myocytes contribute to cerebral blood flow autoregulation in vivo. METHODS: In vivo suppression of cerebrovascular TRPM4 expression was achieved by infusing antisense oligodeoxynucleotides into the cerebral spinal fluid of 400- to 550-g Sprague-Dawley rats at 80 microg x day(-1) for 7 days using an osmotic pump that discharged into the lateral cerebral ventricle. Absolute cerebral blood flow measurements were obtained over a range of mean arterial pressures using fluorescent microsphere methods. RESULTS: Oligonucleotides infused into the cerebrospinal fluid were detected in the smooth muscle cells of pial arteries. Semi-quantitative RT-PCR indicated that the message for TRPM4 was decreased in the cerebral arteries of antisense-treated rats. Myogenic constriction was decreased by 70% to 85% in cerebral arteries isolated from TRPM4 antisense- compared with control sense-treated rats. Cerebral blood flow was significantly greater in TRPM4 antisense- versus sense-treated rats at resting and elevated mean arterial pressures, indicating that autoregulatory vasoconstrictor activity was compromised in TRPM4 antisense-treated animals. CONCLUSIONS: In vivo suppression of TRPM4 decreases cerebral artery myogenic constrictions and impairs autoregulation, thus implicating TRPM4 channels and myogenic constriction as major contributors to cerebral blood flow regulation in the living animal.