During cold exposure, cutaneous blood flow is reduced to prevent heat loss. This is mediated by increased sympathetic tone and a cold-induced sensitization of cutaneous arteries to constriction by norepinephrine. The latter effect is mediated by cold-induced amplification of (alpha2-adrenergic receptor (alpha2-AR) function. Although alpha2-ARs comprise 3 subtypes, only alpha2C-ARs respond to cold. Although alpha2C-ARs are not functional at 37 degrees C, they are entirely responsible for the cold-induced amplification of alpha2-AR constriction. At 37 degrees C, alpha2C-ARs are retained in the transGolgi network. Cooling causes alpha2C-AR translocation to the cell surface where they can respond to stimulation. The functional rescue of alpha2C-ARs is mediated by cold-induced activation of RhoA and rho kinase (ROCK). ROCKI inhibition by pharmacological blockade or RNA interference prevents cold-induced mobilization of alpha2C-ARs and cold-induced constriction in cutaneous arteries. We now demonstrate that cooling of tail arteries causes a rapid increase in ROS activity in VSM mitochondria, which precedes RhoA activation. Indeed, inhibition of ROS activity abolished cold-induced activation of RhoA and the functional rescue of alpha2C-ARs. The rescue of alpha2C-ARs was also reduced by a tyrosine kinase inhibitor. We propose that cold stimulates mitochondrial generation of ROS, causing transactivation of a receptor tyrosine kinase and activation of RhoA/ROCKI, enabling the spatial and functional rescue of alpha2C-ARs. We have also identified a novel cyclic AMP signaling pathway in cutaneous VSMs, which activates Rapl and causes profound increases in alpha2C-AR expression. We propose that these novel pathways for regulating the function and expression alpha2C-ARs may contribute to cold-induced vasospasm. Indeed, we present a new model of cold-induced vasospasm, generated by a chemotherapeutic agent that causes Raynaud's Disease in humans. This model displays a selective and dramatic increase in VSM alpha2C-AR activity, which precipitate vasospasm of cutaneous arteries.
Three specific aims are proposed to pursue these novel and exciting findings and to investigate their physiological and pathophysiological significance.
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