Silent α2C-adrenergic receptors enable cold-induced vasoconstriction in cutaneous arteries

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Abstract
Cold constricts cutaneous blood vessels by increasing the reactivity of smooth muscle α2-adrenergic receptors (α2-ARs). Experiments were performed to determine the role of α2-AR subtypes (α2A-, α2B-, α2C-ARs) in this response. Stimulation of α1-ARs by phenylephrine or α2-ARs by UK-14,304 caused constriction of isolated mouse tail arteries mounted in a pressurized myograph system. Compared with proximal arteries, distal arteries were more responsive to α2-AR activation but less responsive to activation of α1-ARs. Cold augmented constriction to α2-AR activation in distal arteries but did not affect the response to α1-AR stimulation or the level of myogenic tone. Western blot analysis demonstrated expression of α2A- and α2C-ARs in tail arteries: expression of α2C-ARs decreased in distal compared with proximal arteries, whereas expression of the glycosylated form of the α2A-AR increased in distal arteries. At 37°C, α2-AR-induced vasoconstriction in distal arteries was inhibited by selective blockade of α2A-ARs (BRL-44408) but not by selective inhibition of α2B-ARs (ARC-239) or α2C-ARs (MK-912). In contrast, during cold exposure (28°C), the augmented response to UK-14,304 was inhibited by the α2C-AR antagonist MK-912, which selectively abolished cold-induced amplification of the response. These experiments indicate that cold-induced amplification of α2-ARs is mediated by α2C-ARs that are normally silent in these cutaneous arteries. Blockade of α2C-ARs may prove an effective treatment for Raynaud's Phenomenon.