Adenosine inhibits collagen and total protein synthesis in vascular smooth muscle cells

The objective of this study was to characterize the effects of exogenous, drug-induced and cAMP-adenosine pathway-derived adenosine on collagen synthesis by and hypertrophy of vascular smooth muscle cells (SMCs). Confluent vascular SMCs were stimulated with 2.5% fetal calf serum in the presence and absence of adenosine receptor agonists [adenosine, 2-chloroadenosine, N-6-cyclopentyladenosine, 5'-N-ethylcarboxamidoadenosine, 5'-N-methylcarboxamidoadenosine, and 2-p-(2-carboxyethyl)phenethylamino-5'-N-adenosine], drugs that increase levels of endogenous adenosine [erythro-9-(2-hydroxy-3-nonyl) adenine, dipyridamole, and iodotubericidin], and cAMP (increases adenosine by conversion to AMP and hence to adenosine via the cAMP-adenosine pathway). Adenosine receptor agonists inhibited fetal calf serum-induced collagen and total protein synthesis las assessed by [H-3]proline and [H-3]leucine incorporation, respectively) with a relative potency profile consistent with the effects being mediated by adenosine A(2B) receptors. Erythro-9-(2-hydroxy-3-nonyl) adenine, dipyridamole, iodotubericidin, and cAMP also inhibited collagen and total protein synthesis. The effects of 2-chloroadenosine, erythro-9-(2-hydroxy-3-nonyl) adenine, iodotubericidin, and cAMP on collagen and total protein synthesis were attenuated by KF17837 and 1,3-dipropyl-8-p-sulfophenylxanthine (selective and nonselective A, receptor antagonists, respectively) but not by 8-cyclopentyl-1,3-dipropylxanthine (selective A(1) receptor antagonist). These studies indicate that exogenous, drug-induced and cAMP-adenosine pathway-derived adenosine inhibit vascular SMC collagen synthesis and hypertrophy via A(2B) receptors, Thus, exogenous A(2B) receptor agonists and drugs that modulate endogenous adenosine levels may protect against vasoocclusive disorders by attenuating extracellular matrix synthesis by and cellular hypertrophy of vascular SMCs. Moreover, the cAMP-adenosine pathway may protect against vascular hypertrophy.