title: Rho kinase activity governs arteriolar myogenic depolarization.
abstract: Cerebral arterioles contribute critically to regulation of local and global blood flow within the brain. Dysfunction of these blood vessels is implicated in numerous cardiovascular diseases. However, treatments are limited due to incomplete understanding of fundamental control mechanisms at this level of circulation. Emerging evidence points to a key role of Rho-associated protein kinase in regulation of microvascular contractility. This study sought to decipher the mechanisms of Rho-associated protein kinase-mediated myogenic vasoconstriction in cerebral parenchymal arterioles. Here, we report that the Rho-associated protein kinase inhibitor H1152 strongly attenuated pressure-induced constriction, cytosolic [Ca2+] increases, and depolarization of isolated parenchymal arterioles. Further, the RhoA activator CN03 potentiated parenchymal arteriole myogenic constriction and depolarization, indicating important involvement of RhoA/Rho-associated protein kinase signaling in myogenic excitation-contraction mechanisms. Because of the well-established role of TRPM4 in pressure-induced depolarization, possible modulatory effects of Rho-associated protein kinase on TRPM4 currents were explored using patch clamp electrophysiology. TRPM4 currents were suppressed by H1152 and enhanced by CN03. Finally, H1152 elevated the apparent [Ca2+]-threshold for TRPM4 activation, suggesting that Rho-associated protein kinase activates TRPM4 by increasing its Ca2+-sensitivity. Our results support a novel mechanism whereby Rho-associated protein kinase-mediated myogenic vasoconstriction occurs primarily through activation of TRPM4 channels, smooth muscle depolarization, and cytosolic [Ca2+] increases in cerebral arterioles.
authors.affiliation: Department of Pharmacology, University of Vermont, Burlington, VT, USA.
authors.forename: Yao
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pharmacology, University of Vermont, Burlington, VT, USA joe.brayden@uvm.edu.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Brayden
mesh_terms: D000818:Animals; D001160:Arterioles / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D008564:Membrane Potentials / Q000502:physiology; D009119:Muscle Contraction / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D018408:Patch-Clamp Techniques; D051381:Rats; D050053:TRPM Cation Channels / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects*; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D050053:TRPM Cation Channels; C500239:TRPM4 protein, rat; D054460:rho-Associated Kinases; D002118:Calcium
keywords: Cerebral arteriole; Rho kinase; TRPM4; depolarization; myogenic