Chronic hypoxia opposes pregnancy-induced increase in uterine artery vasodilator response to flow

Abstract

We tested the hypotheses that pregnancy increases the uterine artery (UA) vasodilator response to flow and that this increase is impaired under conditions of chronic hypoxia (30 days, simulated elevation 3,960 m). UA were isolated from 24 normoxic or chronically hypoxic midpregnant guinea pigs and studied with the use of pressure myography. Normoxic pregnancy increased UA flow vasodilator response and protected against a rise in wall shear stress (WSS). Chronic hypoxia opposed these effects, prompting vasoconstriction at high flow and increasing WSS above levels seen in normoxic pregnant UA. The nitric oxide synthase inhibitor N(G)-nitro-l-arginine (l-NNA) eliminated the pregnancy-associated increase in flow vasodilation in normoxic UA, suggesting that increased nitric oxide production was responsible. The considerable residual vasodilation after nitric oxide synthase and cyclooxygenase inhibition implicated endothelial-derived hyperpolarizing factor (EDHF) as an additional contributor to flow vasodilation. l-NNA increased flow vasodilation in UA from chronically hypoxic animals, suggesting that chronic hypoxia may have lowered EDHF or elevated peroxynitrite production. In conclusion, flow is an important physiological vasodilator for the acute and more chronic UA dimensional changes required to increase uteroplacental blood flow during normal pregnancy. Chronic hypoxia may be a mechanism that opposes the pregnancy-associated rise in UA flow vasodilation, thereby increasing the incidence of preeclampsia and intrauterine growth restriction at a high altitude.

Greater uterine artery blood flow during pregnancy in multigenerational (Andean) than shorter-term (European) high-altitude residents

“…Although the major resistance vessels in the human uteroplacental circulation are the arcuate, basilar (or spiral arteries in complicated pregnancies), the main UA also contributes, since in species with hemochorial placentation, two-thirds of uteroplacental vascular resistance resides upstream of the terminal, uteroplacental channels (26). The larger UA diameters in the Andean compared with the European women may have been due to greater vessel growth, differences in the levels of circulating or locally produced vasodilators and vasoconstrictors, and/or changes in sensitivity to such substances or to other physiological stimuli, such as blood flow itself (24,34,43). Such possibilities remain to be addressed in future studies.…”

“…However, the mechanisms by which chronic hypoxia slows fetal growth are unknown. Human and experimental animal data indicate that alterations in maternal circulatory responses to pregnancy are likely involved; in species experiencing a reduction in fetal growth at high altitude, chronic hypoxia decreases the normal pregnancy-associated rise in uterine artery (UA) nitric oxide production, halves the mid-gestation increase in UA DNA synthesis, and inhibits flow-induced UA vasodilation (19,24,43). Consistent with these findings, Colorado high-altitude residents have smaller UA diameters and lower blood flows near term than lowaltitude controls (46).…”

Diminished NO release in chronic hypoxic human endothelial cells

“…Endotheliumderived NO was suggested to contribute to acute hypoxic vasodilation in human umbilical vein ring segments (32), whereas NO synthase (NOS) inhibition hardly influenced flowevoked endothelium-dependent vasodilation in porcine coronary resistance arteries (21). In chronic hypoxia, in vivo studies have suggested that NO-dependent vasodilatation is decreased in the rat aorta and in uterine arteries from pregnant guinea pigs (31,56), whereas it appears to be increased in pregnant ovine uterine arteries (58) and small mesenteric arteries (13) and in fetal guinea pig hearts (52). Hypoxia was reported to increase NO end products in pregnant ovine uterine arteries (58), and direct measurements with microsensors in mesenteric arteries also suggested that NO was increased (13), whereas fluorescence measurements revealed that NO was decreased in pulmonary arteries from chronic hypoxic rats (35).…”

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

“…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).…”