Adenosine Inhibits Collagen and Total Protein Synthesis in Vascular Smooth Muscle Cells

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Abstract
—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 -ethylcarboxamino 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 (as assessed by [ 3 H]proline and [ 3 H]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 2 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.