Brain tissue is extremely sensitive to alterations in blood flow. Autoregulatory mechanisms inherent to the vessel wall contribute the maintenance of relatively constant blood flow in cerebral blood vessels. For example, small arteries constrict in response to increases in intraluminal pressure, thereby preventing increases in flow during increased perfusion pressure. This behavior is known as the vascular myogenic response. Previous studies have established that myogenic vasoconstriction results from depolarization of vascular smooth muscle (VSM) associated with mechanical stretch. Depolarization initiates calcium influx via voltage-dependent calcium channels, thereby activating the smooth muscle contractile apparatus. The ionic mechanisms contributing to VSM cell depolarization following membrane stretch are not fully described. The current proposal tests the hypothesis that a recently described member of the transient receptor potential (TRP) family of ion channels contributes to myogenic vasoconstriction of cerebral resistance vessels. Cloned TRPM4b channels expressed in HEK-293 cells are selective for monovalent cations and are activated by mechanical stretch. Activation of these channels initiates a depolarizing cation current, suggesting that TRPM4b may contribute to VSM cell depolarization associated with increases in intraluminal pressure. It is anticipated that these studies will generate significant new information regarding the role of mechanosensitive cation channels in the regulation of VSM membrane potential and the regulation of cerebral blood flow.
