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(Hypertension. 2000;35:262.)
© 2000 American Heart Association, Inc.

Scientific Contributions

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

Raghvendra K. Dubey; Delbert G. Gillespie; Zaichuan Mi; Marinella Rosselli; Paul J. Keller; Edwin K. Jackson

From the Departments of Medicine (R.K.D., D.G.G., Z.M., E.K.J.) and Pharmacology (E.K.J.), Center for Clinical Pharmacology, University of Pittsburgh Medical Center (Pa), and Department of Obstetrics and Gynecology, Clinic for Endocrinology, University Hospital Zurich (Switzerland) (R.K.D., M.R., P.J.K).

Correspondence to Dr Raghvendra K. Dubey, Department of Obstetrics and Gynecology, Clinic for Endocrinology, NORD-1 (D217), Frauenheilkunde, FrauenKlinikstrasse 10, University Hospital Zurich, CH-8091 Zurich, Switzerland. E-mail rag{at}fhk.smtp.usz.ch

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; A₁/A₂ adenosine receptor antagonist), KF17837 (10 nmol/L; selective A₂ adenosine receptor antagonist), 8-cyclopentyl-1,3-dipropylxanthine (10 nmol/L; selective A₁ 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 A₂ adenosine receptors. Thus, the cAMP-adenosine pathway may contribute importantly to the antivasooclusive effects of estradiol.

Key Words: hormones • cyclic AMP • adenosine • muscle, smooth • receptors, adenosine • vascular remodeling

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