RESUMEN
Sequential conversion of estradiol-17ß 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 ß-adrenergic receptors (ARs), we investigated whether the endothelial α- or ß-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)-, ß(2)-, and ß(3)-ARs but not α(1)- and ß(1)-ARs. Levels of ß(2)-ARs and ß(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 (ß-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. ß(2)-AR and ß(3)-AR antagonists (ICI 118 551and SR 59230A, respectively) abrogated the mitogenic effects of both 2-OHE(2) and 4-OHE(2). Stimulation of ß(2)-ARs and ß(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 ß(2)-ARs and ß(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.