Journal
CIRCULATION RESEARCH
Volume 94, Issue 10, Pages 1367-1374Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.RES.0000128407.45014.58
Keywords
raynaud phenomenon; siRNA; thermoregulation; HEK293 cells
Funding
- NHLBI NIH HHS [HL67331] Funding Source: Medline
- NIAMS NIH HHS [AR46126] Funding Source: Medline
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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 37degreesC 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 37degreesC but dramatically reduced the augmented responses to the agonist at 28degreesC. After Rho kinase inhibition, cooling no longer increased constriction evoked by alpha2-AR stimulation. Cooling (to 28degreesC) activated Rho in VSM cells and increased the calcium sensitivity of constriction in alpha toxin-permeabilized arteries. Stimulation of alpha 2-ARs in VSM cells had no effect on Rho activity or calcium sensitivity at 37degreesC or 28degreesC. In HEK293 cells transfected with alpha2C-ARs, cooling (to 28degreesC) 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 28degreesC but not 37degreesC. 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.
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