B‐Myb regulates the A2B adenosine receptor in vascular smooth muscle cells

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Abstract
The A2B adenosine receptor (A2BAR) has been described to control various vascular functions, including inhibition of smooth muscle cell proliferation. Here, we sought to understand the regulation of A2BAR gene expression in aortic vascular smooth muscle cells (VSMCs), with a focus on the proliferation phase. Assays with A2BAR‐β‐gal aortic VSMCs, in which the endogenous A2BAR gene promoter drives the expression of prokaryotic β‐galactosidase (β‐gal) instead of the endogenous A2BAR gene, show that β‐gal expression is upregulated when the cells are induced to exit from cell cycle arrest. Similarly, the level of A2BAR mRNA is upregulated in proliferating primary aortic VSMCs. In search of related mechanisms, it was noted that the A2BAR gene promoter contains several putative binding sites for the proliferation‐inducing transcription factor, B‐Myb. Using a clone of the 5′ region upstream of the mouse A2BAR gene linked to a reporter gene, B‐Myb site deletion mutants were generated. It was determined that B‐Myb upregulates the A2BAR gene promoter, and specific promoter binding sites were identified as functional. In accordance, B‐Myb also elevates endogenous A2BAR mRNA and receptor activity, and this activity decreases cell proliferation. Our data are novel in that they show that this proliferation‐inhibiting A2BAR is itself an inducible receptor regulated by B‐Myb. J. Cell. Biochem. 103: 1962–1974, 2007.