This review will consider whether nitric oxide (NO) contributes to maternal systemic vasodilation during pregnancy, regulates uterine and fetoplacental blood flow, and is involved in uterine quiescence prior to parturition. Also, whether a deficiency of NO contributes to the hypertensive disorder of pregnancy, preeclampsia, will be considered. The biosynthesis of NO increases in gravid rats and sheep, but the status in normal human pregnancy and preeclampsia is controversial. NO contributes to maternal systemic vasodilation and reduced vascular reactivity during normal pregnancy; however, the relative contribution of NO is variable depending on the animal species, vascular bed, and vessel size. Impaired relaxation responses to acetylcholine, but not bradykinin or NO donors, are observed in small arteries from women with preeclampsia, suggesting a receptor or signal transduction defect, although NO may play little, if any, role here. Uterine arteries have increased endothelial nitric oxide synthase (NOS) activity, protein expression, and guanosine 3',5'-cyclic monophosphate production during pregnancy; however, whether these mediate uterine vasodilation during pregnancy remains to be established. NOS is expressed in the human placental syncytiotrophoblast and in the fetoplacental and umbilical vascular endothelium where basal production of NO contributes to low fetoplacental vascular resistance. Controversy exists over the status of placental NOS in preeclampsia, although an abnormality of umbilical NOS activity is likely. Finally, the uterus has NOS activity, which decreases at the end of gestation, and exogenous NO relaxes the myometrium, but whether endogenous NO contributes to uterine quiescence during pregnancy has yet to be confirmed.

Estradiol-17 ␤ (E 2 ␤ ), a potent vasodilator, has its greatest effects on the uterine vasculature, blood flow (UBF) increasing Ն 10-fold. The mechanism(s) responsible for E 2 ␤ -induced vasodilation is unclear. We determined if nitric oxide (NO)-induced increases in cGMP modulate estrogen-induced increases in UBF, and if cyclooxygenase inhibition modifies E 2 ␤ responses. Nonpregnant ( n ϭ 15) and pregnant ( n ϭ 8) ewes had flow probes implanted on main uterine arteries and catheters in branches of the uterine vein and artery bilaterally for blood sampling and infusion of the NO synthase inhibitor L -nitro-arginine methyl ester ( L -NAME), respectively. In nonpregnant ewes E 2 ␤ (1 g/kg) caused parallel increases ( P Ͻ 0.001) in UBF (15 Ϯ 3 to 130 Ϯ 16 ml/ min) and uterine cGMP secretion (23 Ϯ 10 to 291 Ϯ 38 pmol/ min); uterine venous cGMP also rose (4.98 Ϯ 1.4 to 9.43 Ϯ 3.2 pmol/ml; P Ͻ 0.001). Intra-arterial L -NAME partially inhibited increases in UBF dose-dependently (r ϭ 0.66, n ϭ 18, P Յ 0.003) while completely inhibiting cGMP secretion ( P ϭ 0.025). Indomethacin, 2 mg/kg intravenously, did not alter E 2 ␤ -induced responses. After E 2 ␤ -induced increases in UBF, intraarterial L -NAME partially decreased UBF dose dependently (r ϭ 0.73, n ϭ 46, P Ͻ 0.001) while inhibiting cGMP secretion (178 Ϯ 48 to 50 Ϯ 24 pmol/min; n ϭ 5, P ϭ 0.006); both were reversed by L -arginine. In pregnant ewes, E 2 ␤ increased UBF and venous cGMP (9.1 Ϯ 0.96 to 13.2 Ϯ 0.96 pmol/ml, P Ͻ 0.01); however, intraarterial L -NAME decreased basal cGMP secretion 66% (P ϭ 0.02), but not UBF. Acute estrogen-induced increases in UBF are associated with NO-dependent increases in cGMP synthesis, but other mechanisms may also be involved. However, vasodilating prostanoids do not appear to be important. In ovine pregnancy NO is not essential for maintaining uteroplacental vasodilation. ( J. Clin. Invest. 1996. 98:2158-2166.)

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Rapid uterine vasodilatation after estrogen administration is believed to be mediated by endothelial production of nitric oxide (NO) via endothelial NO synthase (eNOS). However, the mechanism(s) by which estrogen activates eNOS in uterine artery endothelial cells (UAEC) is unknown. In this study, we observed that estradiol-17beta (E2) and E2-BSA rapidly (<2 min) increased total NOx production in UAEC in vitro. This was associated with rapid eNOS phosphorylation and activation but was unaltered by pretreatment with actinomycin-D. Estrogen receptor-alpha protein was detectable in isolated plasma membrane proteins by immunoblotting, and E2-BSA-fluorescein isothiocyanate binding was evident on the plasma membrane of UAEC. E2 did not mobilize intracellular Ca2+, but E2 and ionomycin in combination induced greater eNOS phosphorylation than either E2 or ionomycin alone. E2 did not stimulate rapid Akt phosphorylation. E2 stimulated rapid ERK2/1 activation in a time- and dose-dependent manner, with maximal responses observed at 5-10 min with E2 (10 nm to 1 microm) treatment. Acute activation of eNOS and NOx production by E2 could be inhibited by PD98059 but not by LY294002. When E2-BSA was applied, similar responses in NOx production, eNOS, and ERK2/1 activation to those of E2 were achieved. In addition, E2 and E2-BSA-induced ERK2/1 activation and ICI 182,780 could inhibit NOx production by E2. Thus, acute activation of eNOS to produce NO in UAEC by estrogen is at least partially through an ERK pathway, possibly via estrogen receptor localized on the plasma membrane. This pathway may provide a novel mechanism for NO-mediated rapid uterine vasodilatation by estrogen.