title: Estradiol inhibits smooth muscle cell growth in part by activating the cAMP-adenosine pathway.
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 micromol/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 micromol/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.
authors.affiliation: Departments of Medicine, University of Pittsburgh Medical Center (Pa), and Department of Obstetrics and Gynecology, Clinic for Endocrinology, University Hospital Zurich, Switzerland. rag@fhk.smtp.usz.ch
authors.forename: R K
authors.initials: RK
authors.lastname: Dubey
authors.forename: D G
authors.initials: DG
authors.lastname: Gillespie
authors.forename: Z
authors.initials: Z
authors.lastname: Mi
authors.forename: M
authors.initials: M
authors.lastname: Rosselli
authors.forename: P J
authors.initials: PJ
authors.lastname: Keller
authors.forename: E K
authors.initials: EK
authors.lastname: Jackson
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001011:Aorta / Q000166:cytology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D003634:DDT / Q000031:analogs & derivatives / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology*; D005326:Fetal Proteins / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000737:chemistry / Q000166:cytology* / Q000201:enzymology*; D011392:Proline / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D013873:Thionucleotides / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism / Q000494:pharmacology; D014316:Tritium; D014970:Xanthines / Q000494:pharmacology
chemical_list: D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D005326:Fetal Proteins; D018047:Receptors, Purinergic P1; D013873:Thionucleotides; D014970:Xanthines; D014316:Tritium; C081198:KF 17837; D005576:Colforsin; C016957:adenosine-3',5'-cyclic phosphorothioate; D004958:Estradiol; C000849:bis(p-chlorophenyl)acetic acid; D011392:Proline; C051360:1,3-dipropyl-8-cyclopentylxanthine; D003634:DDT; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D000241:Adenosine; D013936:Thymidine