2',3'-cAMP, 3'-AMP, and 2'-AMP Inhibit Human Aortic and Coronary Vascular Smooth Muscle Cell Proliferation via A2B Receptors

Edwin K Jackson, Jin Ren, Delbert G Gillespie

Am J Physiol Heart Circ Physiol. 2011 Aug;301(2):H391-401.

PMID: 21622827


Rat vascular smooth muscle cells (VSMCs) from renal microvessels metabolize 2',3'-cAMP to 2'-AMP and 3'-AMP, and these AMPs are converted to adenosine that inhibits microvascular VSMC proliferation via A(2B) receptors. The goal of this study was to test whether this mechanism also exists in VSMCs from conduit arteries and whether it is similarly expressed in human vs. rat VSMCs. Incubation of rat and human aortic VSMCs with 2',3'-cAMP concentration-dependently increased levels of 2'-AMP and 3'-AMP in the medium, with a similar absolute increase in 2'-AMP vs. 3'-AMP. In contrast, in human coronary VSMCs, 2',3'-cAMP increased 2'-AMP levels yet had little effect on 3'-AMP levels. In all cell types, 2',3'-cAMP increased levels of adenosine, but not 5'-AMP, and 2',3'-AMP inhibited cell proliferation. Antagonism of A(2B) receptors (MRS-1754), but not A(1) (1,3-dipropyl-8-cyclopentylxanthine), A(2A) (SCH-58261), or A(3) (VUF-5574) receptors, attenuated the antiproliferative effects of 2',3'-cAMP. In all cell types, 2'-AMP, 3'-AMP, and 5'-AMP increased adenosine levels, and inhibition of ecto-5'-nucleotidase blocked this effect of 5'-AMP but not that of 2'-AMP nor 3'-AMP. Also, 2'-AMP, 3'-AMP, and 5'-AMP, like 2',3'-cAMP, exerted antiproliferative effects that were abolished by antagonism of A(2B) receptors with MRS-1754. In conclusion, VSMCs from conduit arteries metabolize 2',3'-cAMP to AMPs, which are metabolized to adenosine. In rat and human aortic VSMCs, both 2'-AMP and 3'-AMP are involved in this process, whereas, in human coronary VSMCs, 2',3'-cAMP is mainly converted to 2'-AMP. Because adenosine inhibits VSMC proliferation via A(2B) receptors, local vascular production of 2',3'-cAMP may protect conduit arteries from atherosclerosis.

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