International Journal of Molecular Sciences Review Estrogen Receptors and Estrogen-Induced Uterine Vasodilation in Pregnancy Jin Bai 1 , Qian-Rong Qi 1 , Yan Li 1, Robert Day 1, Josh Makhoul 1 , Ronald R. Magness 2 and Dong-bao Chen 1,* 1 Department of Obstetrics & Gynecology, University of California, Irvine, CA 92697, USA;
[email protected] (J.B.);
[email protected] (Q.-R.Q.);
[email protected] (Y.L.);
[email protected] (R.D.);
[email protected] (J.M.) 2 Department of Obstetrics & Gynecology, University of South Florida, Tampa, FL 33612, USA;
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[email protected]; Tel.: +949-824-2409 Received: 27 May 2020; Accepted: 15 June 2020; Published: 18 June 2020 Abstract: Normal pregnancy is associated with dramatic increases in uterine blood flow to facilitate the bidirectional maternal–fetal exchanges of respiratory gases and to provide sole nutrient support for fetal growth and survival. The mechanism(s) underlying pregnancy-associated uterine vasodilation remain incompletely understood, but this is associated with elevated estrogens, which stimulate specific estrogen receptor (ER)-dependent vasodilator production in the uterine artery (UA). The classical ERs (ERα and ERβ) and the plasma-bound G protein-coupled ER (GPR30/GPER) are expressed in UA endothelial cells and smooth muscle cells, mediating the vasodilatory effects of estrogens through genomic and/or nongenomic pathways that are likely epigenetically modified. The activation of these three ERs by estrogens enhances the endothelial production of nitric oxide (NO), which has been shown to play a key role in uterine vasodilation during pregnancy. However, the local blockade of NO biosynthesis only partially attenuates estrogen-induced and pregnancy-associated uterine vasodilation, suggesting that mechanisms other than NO exist to mediate uterine vasodilation.