A(2B) receptors mediate antimitogenesis in vascular smooth muscle cells

Adenosine inhibits growth of vascular smooth muscle cells. The goals of thi s study were to determine which adenosine receptor subtype mediates the ant imitogenic effects of adenosine and to investigate the signal transduction mechanisms involved. In rat aortic vascular smooth muscle cells, platelet-d erived growth factor-BB (PDGF-BB) (25 ng/mL) stimulated DNA synthesis ([H-3 ]thymidine incorporation), cellular proliferation (cell number), collagen s ynthesis ([H-3]proline incorporation), total protein synthesis ([H-3]leucin e incorporation), and mitogen-activated protein (MAP) kinase activity. The adenosine receptor agonists 2-chloroadenosine and 5'-N-methylcarboxamidoade nosine, but not N-6-cyclopentyladenosine or CGS21680, inhibited the growth effects of PDGF-BB, an agonist profile consistent with an A(2B) receptor-me diated effect. The adenosine receptor antagonists KF17837 and 1,3-dipropyl- 8-p-sulfophenylxanthine, but not 8-cyclopentyl-1,3-dipropylxanthine, blocke d the growth-inhibitory effects of 2-chloroadenosine and 5'-N-methylcarboxa midoadenosine, an antagonist profile consistent with an A(2) receptor-media ted effect. Antisense, but not sense or scrambled, oligonucleotides to the A(2B) receptor stimulated basal and PDGF-induced DNA synthesis, cell prolif eration, and MAP kinase activity. Moreover, the growth-inhibitory effects o f 2-chloroadenosine, 5'-N-methylcarboxamidoadenosine, and erythro-9-(2-hydr oxy-3-nonyl) adenine plus iodotubericidin (inhibitors of adenosine deaminas e and adenosine kinase, respectively) were abolished by antisense, but not scrambled or sense, oligonucleotides to the A(2B) receptor. Our findings st rongly support the hypothesis that adenosine causes inhibition of vascular smooth muscle cell growth by activating A(2B) receptors coupled to inhibiti on of MAP kinase activity. Pharmacological or molecular biological activati on of A(2B) receptors may prevent vascular remodeling associated with hyper tension, atherosclerosis, and restenosis following balloon angioplasty.