Estradiol inhibits smooth muscle cell growth in part by activating the cAMP-adenosine pathway

Estradiol inhibits smooth muscle cell growth; however, the mechanisms invol ved remain unclear. Because estradiol stimulates cAMP synthesis and adenosi ne inhibits cell growth, we hypothesized that the conversion of cAMP to ade nosine (ie, the cAMP-adenosine pathway) mediates in part the inhibitory eff ects of estradiol on vascular smooth muscle cell growth. To test this hypot hesis, we examined the effects of estradiol (0.001 to 1 mu mol/L) on serum- induced DNA, collagen, and total protein synthesis and cell number in the a bsence and presence of 1,3-dipropyl-8-psulfophenylxanthine (10 nmol/L; A(1) /A(2) adenosine receptor antagonist), KF17837 (10 nmol/L; selective A(2) ad enosine receptor antagonist), 8-cyclopentyl-1,3-dipropylxanthine (10 nmol/L ; selective A(2) adenosine receptor antagonist), and 2',5'-dideoxyadenosine (10 mu mol/L; adenylyl cyclase inhibitor). Estradiol inhibited all measure s of cell growth, and the concentration-dependent inhibitory curves for est radiol were shifted to the right (P<0.05) by 1,3-dipropyl-8-psulfophenylxan thine, KF17837, and 2',5'-dideoxyadenosine but not by 8-cyclopentyl-1,3-dip ropylxanthine. Moreover, the inhibitory effects of estradiol were enhanced by stimulation of adenylyl cyclase with forskolin and by inhibition of aden osine metabolism with erythro-9-(2-hydroxy-3-nonyl)adenine plus iodotuberic idin (adenosine deaminase and kinase inhibitors, respectively), Estradiol a lso 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 s mooth muscle cell growth via A(2) adenosine receptors. Thus, the cAMP-adeno sine pathway may contribute importantly to the antivasooclusive effects of estradiol.