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. In this review, we summarize the literature on the role of NO in ER-mediated mechanisms controlling estrogen-induced and pregnancy-associated uterine vasodilation and our recent work on a “new” UA vasodilator hydrogen sulfide (H2S) that has dramatically changed our view of how estrogens regulate uterine vasodilation in pregnancy.
Highlights
During the ovarian cycle, follicular development accompanies phasic persistent hyperemia in the uterine vascular bed
The biological effects of estrogen are mediated by multiple estrogen receptor (ER) that activate multiple signaling pathways under the influence of physiological and pathophysiological conditions, adding more complexity to the understanding of estrogen-induced uterine vasodilation
Estrogens and their metabolites are potent uterine vasodilators in the nonpregnant state, and these effects are further augmented during pregnancy
Summary
Follicular development accompanies phasic persistent hyperemia in the uterine vascular bed. NO inhibition maximally attenuates only ~79% of the estrogen-induced rise in UtBF [32] and modestly (~26%) inhibits baseline pregnancy-associated uterine vasodilation [35], clearly suggesting that additional mechanisms are involved. To this end, our novel work has recently identified that augmented hydrogen sulfide (H2S) production functions as a “new” UA vasodilator [37], which may offer great potential for uterine hemodynamic regulation. Sci. 2020, 21, 4349 on the potential clinic implications of dysregulated ER-mediated estrogen signaling in hypertensive pregnancy complications
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