title: Rho kinase mediates cold-induced constriction of cutaneous arteries: role of alpha2C-adrenoceptor translocation.
abstract: Cold-induced vasoconstriction in cutaneous blood vessels is mediated in part by increased activity of vascular smooth muscle alpha2-adrenoceptors (VSM alpha2-ARs). In mouse cutaneous arteries, alpha2C-ARs are normally silent at 37 degrees C but mediate cold-induced augmentation of alpha2-AR responsiveness. In transfected HEK293 cells, this functional rescue is mediated by cold-induced translocation of alpha2C-ARs from the Golgi to the plasma membrane. Experiments were performed to determine the role of Rho/Rho kinase signaling in this process. Inhibition of Rho kinase (fasudil, Y27632 or H-1152) did not affect constriction of isolated mouse tail arteries to the alpha2-AR agonist UK 14 304 at 37 degrees C but dramatically reduced the augmented responses to the agonist at 28 degrees C. After Rho kinase inhibition, cooling no longer increased constriction evoked by alpha2-AR stimulation. Cooling (to 28 degrees C) activated Rho in VSM cells and increased the calcium sensitivity of constriction in alpha toxin-permeabilized arteries. Stimulation of alpha2-ARs in VSM cells had no effect on Rho activity or calcium sensitivity at 37 degrees C or 28 degrees C. In HEK293 cells transfected with alpha2C-ARs, cooling (to 28 degrees C) stimulated the translocation of alpha2C-ARs to the plasma membrane and this effect was prevented by inhibition of Rho kinase, using fasudil or RNA interference. Consistent with inhibition of the spatial rescue of alpha2C-ARs, fasudil inhibited alpha2-AR-mediated mobilization of calcium in tail arteries at 28 degrees C but not 37 degrees C. Therefore, cold-induced activation of Rho/Rho kinase can mediate cold-induced constriction in cutaneous arteries by enabling translocation of alpha2C-ARs to the plasma membrane and by increasing the calcium sensitivity of the contractile process.
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: S R
authors.initials: SR
authors.lastname: Bailey
authors.forename: A H
authors.initials: AH
authors.lastname: Eid
authors.forename: S
authors.initials: S
authors.lastname: Mitra
authors.forename: S
authors.initials: S
authors.lastname: Flavahan
authors.forename: N A
authors.initials: NA
authors.lastname: Flavahan
mesh_terms: D000818:Animals; D001158:Arteries / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D003080:Cold Temperature; D004791:Enzyme Inhibitors / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D021381:Protein Transport; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction; D012867:Skin / Q000098:blood supply*; D014661:Vasoconstriction / Q000187:drug effects; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D054460:rho-Associated Kinases
chemical_list: C547775:Adra2c protein, mouse; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D018341:Receptors, Adrenergic, alpha-2; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D020741:rho GTP-Binding Proteins