Establishment of the Human Uteroplacental Circulation: A Historical Perspective

The uterine vasculature undergoes marked changes during pregnancy in order to provide the necessary increase in blood flow to support growth and nutrition of the uterus, placenta, and developing fetus. Pregnancy-associated uterine vascular transformations are orchestrated by a complex array of endocrine and cellular mechanisms to bring about structural modifications at the maternal-fetal interface, which collectively lead to development of the uteroplacental circulation. Understanding intrinsic uterine vascular remodeling in pregnancy is essential for understanding the physiologic and pathophysiologic regulation of maternal uterine blood flow. Aberrations of uterine vascular remodeling are potentially involved in the etiology of several pregnancy disorders, for example, preeclampsia, fetal growth restriction, and preterm labor; therefore, it is essential for subspecialist clinicians and investigators interested in reproductive physiology to fully understand the establishment of uteroplacental circulation. The foundational literature in this area is extensive; thus, a succinct review is likely to be a useful resource. Herein, we present and discuss a historical perspective on uterine vascular anatomy, maternal vascular growth associated with decidualization, trophoblast invasion, intervillous circulation, aberrations in uterine vascular modeling, and the clinical implications of improper development of the uteroplacental circulation

Establishment of the Human Uteroplacental Circulation: A Historical Perspective

The uterine vasculature undergoes marked changes during pregnancy in order to provide the necessary increase in blood flow to support growth and nutrition of the uterus, placenta, and developing fetus. Pregnancy-associated uterine vascular transformations are orchestrated by a complex array of endocrine and cellular mechanisms to bring about structural modifications at the maternal-fetal interface, which collectively lead to development of the uteroplacental circulation. Understanding intrinsic uterine vascular remodeling in pregnancy is essential for understanding the physiologic and pathophysiologic regulation of maternal uterine blood flow. Aberrations of uterine vascular remodeling are potentially involved in the etiology of several pregnancy disorders, for example, preeclampsia, fetal growth restriction, and preterm labor; therefore, it is essential for subspecialist clinicians and investigators interested in reproductive physiology to fully understand the establishment of uteroplacental circulation. The foundational literature in this area is extensive; thus, a succinct review is likely to be a useful resource. Herein, we present and discuss a historical perspective on uterine vascular anatomy, maternal vascular growth associated with decidualization, trophoblast invasion, intervillous circulation, aberrations in uterine vascular modeling, and the clinical implications of improper development of the uteroplacental circulation

Effects of the Catechol and Methoxy Metabolites of 17β-Estradiol on Nitric Oxide Production by Ovine Uterine Artery Endothelial Cells

Nitric oxide (NO) production is essential to facilitate rises in uterine blood flow (UBF) during pregnancy. It has been proposed that the metabolites of E2β, 2-hydroxyestradiol (2-OHE2), 4-hydroxyestradiol (4-OHE2), 2-methoxyestradiol (2-ME2), and 4-methoxyestradiol (4-ME2) play a role in mediating vasodilation and rises in UBF during pregnancy. We previously showed that the E2β metabolites stimulate prostacyclin production in pregnancy-derived ovine uterine artery endothelial cells (P-UAECs); however, it is unknown whether the E2β metabolites also induce NO production. Herein, UAECs derived from nonpregnant and pregnant ewes were used to test the hypothesis that E2β metabolites stimulate NO production in a pregnancy-specific manner. Specific estrogen receptor (ER) and adrenergic receptor (AR) antagonists were used to determine the roles of ERs or ARs in E2β metabolite-induced NO production. E2β and its metabolites increased total nitric oxide metabolites (NOx) levels (NO2 + NO3) in P-UAECs, but not in NP-UAECs. Pretreatment with combined 1 µmol/L 1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride (MPP; ER-α antagonist) and 1 µmol/L 4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol (PHTPP; ER-β antagonist) inhibited the rises in NOx levels stimulated by E2β and 2-ME2, but had no effect on 2-OHE2-, 4-OHE2-, or 4-ME2-stimulated rises in NOx levels. Pretreatment with yohimbine (α2-AR antagonist) and propranolol (β2,3-AR antagonist) inhibited the rises in NOx levels stimulated by 2-OHE2, but not by E2β, 4-OHE2, 2-ME2, or 4-ME2. These data demonstrate that E2β metabolites stimulate NO synthesis via ERs or ARs in UAECs in a pregnancy-specific manner, suggesting that these metabolites contribute to rises in vasodilation and UBF during pregnancy

Effects of the Catechol and Methoxy Metabolites of 17β-Estradiol on Nitric Oxide Production by Ovine Uterine Artery Endothelial Cells

Nitric oxide (NO) production is essential to facilitate rises in uterine blood flow (UBF) during pregnancy. It has been proposed that the metabolites of E2β, 2-hydroxyestradiol (2-OHE2), 4-hydroxyestradiol (4-OHE2), 2-methoxyestradiol (2-ME2), and 4-methoxyestradiol (4-ME2) play a role in mediating vasodilation and rises in UBF during pregnancy. We previously showed that the E2β metabolites stimulate prostacyclin production in pregnancy-derived ovine uterine artery endothelial cells (P-UAECs); however, it is unknown whether the E2β metabolites also induce NO production. Herein, UAECs derived from nonpregnant and pregnant ewes were used to test the hypothesis that E2β metabolites stimulate NO production in a pregnancy-specific manner. Specific estrogen receptor (ER) and adrenergic receptor (AR) antagonists were used to determine the roles of ERs or ARs in E2β metabolite-induced NO production. E2β and its metabolites increased total nitric oxide metabolites (NOx) levels (NO2 + NO3) in P-UAECs, but not in NP-UAECs. Pretreatment with combined 1 µmol/L 1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride (MPP; ER-α antagonist) and 1 µmol/L 4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol (PHTPP; ER-β antagonist) inhibited the rises in NOx levels stimulated by E2β and 2-ME2, but had no effect on 2-OHE2-, 4-OHE2-, or 4-ME2-stimulated rises in NOx levels. Pretreatment with yohimbine (α2-AR antagonist) and propranolol (β2,3-AR antagonist) inhibited the rises in NOx levels stimulated by 2-OHE2, but not by E2β, 4-OHE2, 2-ME2, or 4-ME2. These data demonstrate that E2β metabolites stimulate NO synthesis via ERs or ARs in UAECs in a pregnancy-specific manner, suggesting that these metabolites contribute to rises in vasodilation and UBF during pregnancy