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2C-ADRENOCEPTOR EXPRESSION: ROLE IN SERUM INDUCTION IN HUMAN ARTERIOLAR SMOOTH MUSCLE CELLS
* To whom correspondence should be addressed. E-mail: chotani-1{at}medctr.osu.edu.
The physiological role of 
2-adrenoceptors (2-ARs) in cutaneous, arteriolar, vascular smooth muscle cells (VSMs) is to mediate cold-induced constriction. In VSMs cultured from human cutaneous arterioles there is a selective increase in 2C-AR expression following serum stimulation. In the present study, we examined the cellular mechanisms contributing to this response. Serum induction of 2C-ARs was paralleled by increased expression of cyclooxygenase-2 (COX-2), increased release of prostaglandins, and increased intracellular concentration of cyclic AMP (cAMP). Inhibition of COX-2 by acetyl salicylic acid (1 mM), NS-398 (5 µM), or celecoxib (3 µM) abolished the increase in cAMP and markedly reduced 2C-AR induction in response to serum stimulation. The cAMP agonists, forskolin (10 µM), isoproterenol (10 µM), and cholera toxin (0.1 µg/mL) each dramatically increased expression of 2C-ARs in human cutaneous VSMs. The A-kinase inhibitor H-89 (2 µM) inhibited phosphorylation of CREB, but not the increase in 2C-AR expression in response to these agonists. cAMP-dependent but A-kinase independent signaling can involve activation of guanine nucleotide exchange factors for the GTP-binding protein, Rap. Indeed, pull-down assays demonstrated Rap 1 activation by serum and forskolin in VSM. Transient transfections using 2C-AR promoter-luciferase reporter construct demonstrated that Rap 1 increased reporter activity, whereas the A-kinase catalytic subunit decreased reporter activity. These results indicate that cAMP signaling can have dual effects in cutaneous VSMs:activation of 2C-AR transcription mediated by Rap 1 GTPase and suppression mediated by A-kinase. The former effect predominates in serum-stimulated VSMs leading to a COX-2, cAMP and Rap 1-dependent increase in 2C-AR expression. Such increased expression of 2C-ARs may contribute to enhanced cold-induced vasoconstriction and Raynaud's phenomenon.
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