Pregnancy enhances endothelium-dependent relaxation of ovine uterine artery: role of NO and intracellular Ca²⁺

Abstract

The present study tested the hypothesis that the pregnancy-associated increase in endothelium-dependent relaxation of the uterine artery was mediated primarily by an increase in nitric oxide (NO) release, resulting in a reduction in smooth muscle intracellular Ca(2+) concentration ([Ca(2+)](i)). Uterine arteries obtained from nonpregnant and near-term (140 days gestation) pregnant sheep were used. The Ca(2+) ionophore A23187 induced endothelium-dependent relaxations in both nonpregnant and pregnant uterine arteries, with an increased relaxation in the pregnant tissue. In contrast, endothelium-independent relaxations induced by sodium nitroprusside were the same in nonpregnant and pregnant arteries. In addition, removal of the endothelium significantly increased noradrenaline-induced contractions in pregnant, but not nonpregnant, uterine arteries. In accordance, pregnancy increased both basal and A23187-stimulated NO releases in the uterine artery. Simultaneous measurement of tension and [Ca(2+)](i) in the smooth muscle demonstrated a linear correlation with the slope of unity between A23187-induced relaxation and the reduction of [Ca(2+)](i) in both nonpregnant and pregnant uterine arteries. The A23187-induced reduction of [Ca(2+)](i) was significantly enhanced in pregnant, compared with nonpregnant, uterine arteries. The results indicate that pregnancy increases NO release, which, through decreasing [Ca(2+)](i) in the smooth muscle, accounts for the increased endothelium-dependent relaxation of the uterine artery. Signal transduction pathways distal to NO production are not changed by pregnancy.

Simultaneous imaging of [Ca2+]iand intracellular NO production in freshly isolated uterine artery endothelial cells: effects of ovarian cycle and pregnancy

“…Although growth of new vessels as well as remodeling of existing vessels during early pregnancy contributes to the increased UBF, the fact that the period of greatest increase in UBF occurs after the completion of new vessel growth indicates that the maintenance of vasodilation in existing or newly developed vessels is crucial (41). Indirect evidence suggests that pregnancy-and follicular phase-associated elevation in UBF is at least partially mediated by NO (15,22,47).…”

Upregulation of endothelial cell Ca2+signaling contributes to pregnancy-enhanced vasodilation of rat uteroplacental arteries

“…The basal activity of Ca 2ϩ -dependent eNOS of guinea-pig uterine arteries was upregulated fourfold in the course of pregnancy (53). Basal generation of NO was increased in uterine arteries of pregnant animals and attenuated the phenylephrine-induced vasoconstriction (17,29,49,(52)(53)(54). In a previous study of Gokina et al (18), inhibition of basal NO production with N -nitro-L-arginine, a potent inhibitor of NO synthase, significantly enhanced pressure-induced constriction of rat uteroplacental arteries.…”

“…acetylcholine; intraluminal pressure; fura-2; manganese quenching NORMAL PREGNANCY is characterized by dramatic and reversible maternal hemodynamic adaptation, including a substantial augmentation of uterine blood flow, which maintains normal oxygen and nutrient delivery to the growing fetus. In late pregnancy, uterine blood flow increases mostly due to considerable growth and remodeling of the maternal uterine vasculature as well as enhanced vasodilation of the uterine arteries in response to chemical or mechanical stimulation (1,3,4,8,9,32,43,45,46,54). Insufficient structural and/or functional vascular adaptation leads to increased uteroplacental vascular resistance with subsequent intrauterine fetal growth restriction (4,43,46).…”

“…Uterine vasodilation, induced both by chemical (ACh) or mechanical stimulation (shear stress), was significantly enhanced during gestation, suggesting that some common mechanism(s) might underlie the pregnancy-induced adaptive changes in endothelial cell function (1,9,10,30,36,38,49,54). Enhanced release of nitric oxide (NO) and prostacyclin in uterine arteries in response to agonist stimulation has been documented in both animal and human pregnancy and is associated with elevated endothelial NO synthase (eNOS) and cyclooxygenase activity and expression (2,3,29,37,49,53,54,56).…”

Pregnancy attenuates uterine artery pressure-dependent vascular tone: role of PKC/ERK pathway

“…The adaptations in the uterine circulation to pregnancy are complex and are mediated in part by enhanced vasodilation and vascular remodeling. Previous studies (3,47,54,57) have focused on the endothelial adaptation and have shown an increase in endothelial nitric oxide synthesis/release in the uterine artery during pregnancy. The adaptation of smooth muscle contractile mechanisms is less clear.…”