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2-Adrenoceptors in Human Vascular Smooth Muscle Cells
1 Davis Heart and Lung Research Institute, Ohio State University, Columbus, OH, USA
2 INSERM U388, INSERM U388, Institut Louis Bugnard, Toulouse, France
3 Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA
* To whom correspondence should be addressed. E-mail: Chotani-1{at}medctr.osu.edu.
The present study analyzed the regulation of 
2-adrenoceptors (2-ARs) in human vascular smooth muscle cells (VSM). Saphenous veins and dermal arterioles, or VSMs cultured from them, expressed high levels of 2-ARs (2C>2A, RNAse protection assay) and responded to 2-AR stimulation (UK14,304, 1µM) with constriction or calcium mobilization. In contrast, VSMs cultured from the aorta did not express 2-ARs and neither cultured cells nor intact aorta responded to UK14,304. Although 2-ARs (2C>>2A) were detected in the aorta, 2C-ARs were localized by immunohistochemistry to VSMs of adventitial arterioles not aortic media. In contrast to the aorta, aortic arterioles constricted to 2-AR stimulation. Reporter constructs demonstrated higher activity of 2A and 2C-ARs gene promoters in arteriolar compared to 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 p38MAPK (SB202190 2µM or dominant-negative p38MAPK). UK14,304 (1µM) caused calcium mobilization in control and serum-stimulated cells: in control VSMs, the response was inhibited by the 2A-AR antagonist BRL- 44408 (100nM) but not by the 2C-AR antagonist MK-912 (1nM), whereas after serum stimulation, MK-912 (1nM), but not BRL-44408 (100nM) inhibited the response. These results demonstrate site-specific expression of 2-ARs in human VSMs reflecting differential activity of 2-AR gene promoters: high expression and function in venous and arteriolar VSMs, no detectable expression or function in aortic VSMs. 2C-ARs can be dramatically and selectively induced via a p38MAPK-dependent pathway. Therefore, altered expression of 2C-ARs may contribute to pathological changes in vascular function.
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