title: A novel role for an endothelial adrenergic receptor system in mediating catecholestradiol-induced proliferation of uterine artery endothelial cells.
abstract: Sequential conversion of estradiol-17β to its biologically active catecholestradiols, 2-hydroxyestradiol (OHE(2)) and 4-OHE(2), contributes importantly to its angiogenic effects on uterine artery endothelial cells (UAECs) derived from pregnant, but not nonpregnant ewes via an estrogen receptor-independent mechanism. Because catecholestradiols and catecholamines exhibit structural similarities and have high affinity for α- and β-adrenergic receptors (ARs), we investigated whether the endothelial α- or β-ARs mediate catecholestradiol-induced proliferation of P-UAECs and whether catecholamines alter these responses. Western analyses revealed expression of specific AR subtypes in nonpregnant UAECs and P-UAECs, including α(2)-, β(2)-, and β(3)-ARs but not α(1)- and β(1)-ARs. Levels of β(2)-ARs and β(3)-ARs were unaltered by pregnancy, whereas α(2)-ARs were decreased. Norepinephrine and epinephrine increased P-UAEC, but not nonpregnant UAEC proliferation, and these effects were suppressed by propranolol (β-AR blocker) but not phentolamine (α-AR blocker). Catecholamines combinations with 2-OHE(2) or 4-OHE(2) enhanced P-UAEC mitogenesis. Catecholestradiol-induced P-UAEC proliferation was also inhibited by propranolol but not phentolamine. β(2)-AR and β(3)-AR antagonists (ICI 118 551and SR 59230A, respectively) abrogated the mitogenic effects of both 2-OHE(2) and 4-OHE(2). Stimulation of β(2)-ARs and β(3)-ARs using formoterol and BRL 37344 dose-dependently stimulated P-UAEC proliferation, which was abrogated by ICI 118 551 and SR 59230A, respectively. Proliferation effects of both catecholamines and catecholestradiols were only observed in P-UAECs (not nonpregnant UAECs) and were mediated via β(2)-ARs and β(3)-ARs. We demonstrate for the first time convergence of the endothelial AR and estrogenic systems in regulating endothelial proliferation, thus providing a distinct evolutionary advantage for modulating uterine perfusion during stressful pregnancies.
authors.affiliation: Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Sheikh O
authors.initials: SO
authors.lastname: Jobe
authors.forename: Sean N
authors.initials: SN
authors.lastname: Fling
authors.forename: Jayanth
authors.initials: J
authors.lastname: Ramadoss
authors.forename: Ronald R
authors.initials: RR
authors.lastname: Magness
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects; D002393:Estrogens, Catechol / Q000494:pharmacology*; D005260:Female; D023421:Models, Animal; D011247:Pregnancy; D011270:Pregnancy, Animal; D011941:Receptors, Adrenergic / Q000378:metabolism*; D012016:Reference Values; D012680:Sensitivity and Specificity; D012756:Sheep; D055988:Uterine Artery / Q000166:cytology / Q000187:drug effects
chemical_list: D002393:Estrogens, Catechol; D011941:Receptors, Adrenergic