Estradiol Inhibits Smooth Muscle Cell Growth in Part by Activating the cAMP-Adenosine Pathway

Abstract

Abstract —Estradiol inhibits smooth muscle cell growth; however, the mechanisms involved remain unclear. Because estradiol stimulates cAMP synthesis and adenosine inhibits cell growth, we hypothesized that the conversion of cAMP to adenosine (ie, the cAMP-adenosine pathway) mediates in part the inhibitory effects of estradiol on vascular smooth muscle cell growth. To test this hypothesis, we examined the effects of estradiol (0.001 to 1 μmol/L) on serum-induced DNA, collagen, and total protein synthesis and cell number in the absence and presence of 1,3-dipropyl-8- p -sulfophenylxanthine (10 nmol/L; A 1 /A 2 adenosine receptor antagonist), KF17837 (10 nmol/L; selective A 2 adenosine receptor antagonist), 8-cyclopentyl-1,3-dipropylxanthine (10 nmol/L; selective A 1 adenosine receptor antagonist), and 2′,5′-dideoxyadenosine (10 μmol/L; adenylyl cyclase inhibitor). Estradiol inhibited all measures of cell growth, and the concentration-dependent inhibitory curves for estradiol were shifted to the right ( P <0.05) by 1,3-dipropyl-8- p -sulfophenylxanthine, KF17837, and 2′,5′-dideoxyadenosine but not by 8-cyclopentyl-1,3-dipropylxanthine. Moreover, the inhibitory effects of estradiol were enhanced by stimulation of adenylyl cyclase with forskolin and by inhibition of adenosine metabolism with erythro-9-(2-hydroxy-3-nonyl)adenine plus iodotubericidin (adenosine deaminase and kinase inhibitors, respectively). Estradiol also increased levels of cAMP and adenosine, and these effects were blocked by 2′,5′-dideoxyadenosine ( P <0.05). Our results support the hypothesis that estradiol stimulates cAMP synthesis and cAMP-derived adenosine regulates smooth muscle cell growth via A 2 adenosine receptors. Thus, the cAMP-adenosine pathway may contribute importantly to the antivasooclusive effects of estradiol.