Increased uterine artery blood flow in hypoxic murine pregnancy is not sufficient to prevent fetal growth restriction†

Abstract

Incomplete maternal vascular responses to pregnancy contribute to pregnancy complications including intrauterine growth restriction (IUGR) and preeclampsia. We aimed to characterize maternal vascular dysfunction in a murine model of fetal growth restriction as an approach toward identifying targetable pathways for improving pregnancy outcomes. We utilized a murine model of late-gestation hypoxia-induced IUGR that reduced E18.5 fetal weight by 34%. Contrary to our hypothesis, uterine artery blood flow as measured in vivo by Doppler ultrasound was increased in mice housed under hypobaric hypoxia (385 mmHg; 5500 m) vs normoxia (760 mmHg; 0 m). Using wire myography, uterine arteries isolated from hypoxic mice had similar vasodilator responses to the two activators A769662 and acetylcholine as those from normoxic mice, although the contribution of an increase in nitric oxide production to uterine artery vasodilation was reduced in the hypoxic vs normoxic groups. Vasoconstrictor responses to phenylephrine and potassium chloride were unaltered by hypoxia. The levels of activated adenosine monophosphate-activated protein kinase (AMPK) were reduced with hypoxia in both the uterine artery and placenta as measured by western blot and immunohistochemistry. We concluded that the rise in uterine artery blood flow may be compensatory to hypoxia but was not sufficient to prevent fetal growth restriction. Although AMPK signaling was reduced by hypoxia, AMPK was still receptive to pharmacologic activation in the uterine arteries in which it was a potent vasodilator. Thus, AMPK activation may represent a new therapy for pregnancy complications involving reduced uteroplacental perfusion.

AMP‐activated protein kinase activator AICAR attenuates hypoxia‐induced murine fetal growth restriction in part by improving uterine artery blood flow

“…Further, as previously reported and discussed (Lane et al . 2019 b ), our model of hypoxia‐induced fetal growth restriction differs from human hypoxic pregnancy in that the mice have elevated uterine artery blood flow with hypoxia compared to normoxia. Although this model is still useful for identifying strategies for improving uterine artery blood flow, a hypoxia‐induced fetal growth restriction model with reduced uterine artery blood flow would be helpful for validating the present findings.…”

“…2016; Lane et al . 2019 b ). Supporting an additional mechanism for increasing uteroplacental blood flow, AMPK‐activating drugs have also been shown to have pro‐angiogenic effects in the uteroplacental unit (Bourque et al .…”

Cystathionine γ-lyase promotes estrogen-stimulated uterine artery blood flow via glutathione homeostasis

“…Calculated blood flow (mL/min*kg) yielded a coefficient of variation of ~10%, demonstrating technical precision ( Supplemental Fig. S1 ) [ 41 ]. First, we assessed baseline uterine and renal artery parameters for untreated ovariectomized CSE KO and WT animals.…”

High altitude regulates the expression of AMPK pathways in human placenta

“…Such variation suggests that differences among animal models, types of tissues, and the duration or magnitude of hypoxic exposure have dissimilar effects on AMPK activation. We recently reported that in vivo treatment with the AMPK activator, AICAR, prevented half of the hypoxia-elicited decrease in murine fetal growth [24], strongly implicating a role of AMPK in the regulation of fetal growth under hypoxic conditions.…”

“…Studies in pregnant mice under hypoxic conditions revealed similar results as well. One report showed that hypoxia augmented AMPK phosphorylation in the placental labyrinthine zone [23], while a subsequent one showed the opposite effect in murine placental homogenates [24]. Such variation suggests that differences among animal models, types of tissues, and the duration or magnitude of hypoxic exposure have dissimilar effects on AMPK activation.…”