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.