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TRANSLATIONAL PHYSIOLOGY

Regulation of ₂-adrenoceptors in human vascular smooth muscle cells

¹Davis Heart and Lung Research Institute, Ohio State University, Columbus, Ohio 43210; ²Institut National de la Santé et de la Recherche Médicale U388, Institut Louis Bugnard, 31403 Toulouse Cedex 4, France; and ³Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118

Submitted 27 March 2003 ; accepted in final form 22 August 2003

This study analyzed the regulation of ₂-adrenoceptors (₂-ARs) in human vascular smooth muscle cells (VSMs). Saphenous veins and dermal arterioles or VSMs cultured from them expressed high levels of ₂-ARs (_2C > _2A, via RNase protection assay) and responded to ₂-AR stimulation [5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine (UK-14,304, 1 µM)] with constriction or calcium mobilization. In contrast, VSMs cultured from aorta did not express ₂-ARs and neither cultured cells nor intact aorta responded to UK-14,304. Although ₂-ARs (_2C >> _2A) were detected in aortas, _2C-ARs were localized by immunohistochemistry to VSMs of adventitial arterioles and not aortic media. In contrast with aortas, aortic arterioles constricted in response to ₂-AR stimulation. Reporter constructs demonstrated higher activities for _2A- and _2C-AR gene promoters in arteriolar compared with aortic VSMs. In arteriolar VSMs, serum increased expression of _2C-AR mRNA and protein but decreased expression of _2A-ARs. Serum induction of _2C-ARs was reduced by inhibition of p38 mitogen-activated protein kinase (MAPK) with 2 µM SB-202190 or dominant-negative p38 MAPK. UK-14,304 (1 µM) caused calcium mobilization in control and serum-stimulated cells: in control VSMs, the response was inhibited by the _2A-AR antagonist BRL-44408 (100 nM) but not by the _2C-AR antagonist MK-912 (1 nM), whereas after serum stimulation, MK-912 (1 nM) but not BRL-44408 (100 nM) inhibited the response. These results demonstrate site-specific expression of ₂-ARs in human VSMs that reflects differential activity of ₂-AR gene promoters; namely, high expression and function in venous and arteriolar VSMs but no detectable expression or function in aortic VSMs. We found that _2C-ARs can be dramatically and selectively induced via a p38 MAPK-dependent pathway. Therefore, altered expression of _2C-ARs may contribute to pathological changes in vascular function.

microcirculation; MK-912; BRL-44408; p38 mitogen-activated protein kinase

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