Endothelial NO Synthase Augments Fetoplacental Blood Flow, Placental Vascularization, and Fetal Growth in Mice

Abstract

Abstract-It is not known whether eNOS deficiency in the mother or the conceptus (ie, placenta and fetus) causes fetal growth restriction in mice lacking the endothelial NO synthase gene (eNOS knockout [KO]). We hypothesized that eNOS sustains fetal growth by maintaining low fetoplacental vascular tone and promoting fetoplacental vascularity and that this is a conceptus effect and is independent of maternal genotype. We found that eNOS deficiency blunted fetal growth, and blunted the normal increase in umbilical blood flow and umbilical venous diameter and the decrease in umbilical arterial Resistance Index in late gestation (14.5-17.5 days) in eNOS KO relative to C57Bl/6J controls. On day 17.5, fetoplacental capillary lobule length and capillary density in vascular corrosion casts were reduced in eNOS KO placentas. Reduced vascularization may be a result of decreased vascular endothelial growth factor mRNA and protein expression in eNOS KO placentas at this stage. These factors, combined with significant anemia found in eNOS KO fetuses, would be anticipated to reduce fetal oxygen delivery and contribute to the fetal tissue hypoxia that was detected in the heart, lung, kidney, and liver by immunohistochemistry using pimonidazole. Although maternal eNOS deficiency impairs uteroplacental adaptations to pregnancy, maternal genotype was not a significant factor affecting growth in heterozygous conceptuses. This indicates that fetal growth restriction was primarily caused by conceptus eNOS deficiency. In mice, placental hemodynamic and vascular changes with gestation and growth restriction showed strong parallels with human pregnancy. Thus, the eNOS KO model could provide insights into the pathogenesis of human intrauterine growth restriction. and vasculogenesis as shown in other vascular beds studied in adult animals. 13In the current study, we hypothesized that eNOS sustains fetal growth by maintaining low fetoplacental vascular tone and promoting fetoplacental vascularity. We further hypothesized that this is a conceptus effect and is independent of maternal genotype. We used eNOS knockout (KO) pregnancies because eNOS KO fetuses exhibit fetal growth restriction in late gestation, [14][15][16] and pregnant eNOS KO mothers exhibit impaired uteroplacental remodeling and a blunted rise in uteroplacental blood flow and cardiac output. 15,16 However, they neither overexpress sFlt1 mRNA in the placenta 16 nor do they become more hypertensive during pregnancy. [16][17][18] In this study, we quantified umbilical vein blood flow and umbilical artery Resistance Index using micro-ultrasound, visualized the fetoplacental vasculature using vascular corrosion casts, and evaluated hypoxia in the fetus in eNOS KO mice and in the background strain, C57Bl/6J (wild type [WT]). Whether IUGR is secondary to reduced uteroplacental perfusion or is a result of effects of eNOS deficiency in the conceptus in this model is not clear. Thus, crossbreeding experiments were performed to determine the impact of maternal genotype on the fetal phen...

Exercise rescues obese mothers’ insulin sensitivity, placental hypoxia and male offspring insulin sensitivity

“…Structurally, feeding an obesogenic diet during pregnancy has been shown to result in a reduced fetal capillary volume30 which is associated with impaired oxygen delivery31. This supports the idea of a hypoxia-mediated response to maternal obesity in the placenta.…”

Inflammation-induced fetal growth restriction in rats is associated with increased placental HIF-1α accumulation

“…Reduced NO bioavailability is associated with FGR in humans [48–50], and in our earlier work, we showed that GTN prevented inflammation-induced FGR by reducing spiral artery resistance index, placental nitrosative stress, mean arterial pressure and renal structural alterations using the same rat model described here [16]. In another model of FGR, endothelial nitric oxide synthase (eNOS) deficiency has been shown to cause hemodynamic and vascular changes that were linked to placental hypoxia [31, 51, 52]. However, in our inflammation-induced FGR model, the impaired spiral artery remodelling observed [16] does not necessarily indicate that placental hypoxia would occur since remodelling and subsequent dilation of the spiral arteries alone is thought to have a minimal effect on total blood flow [53].…”

Treating the dysfunctional placenta

“…Furthermore, spiral artery remodelling and fetoplacental vascular development are impaired in eNOS −/− vs WT mice, in common with human FGR (Kulandavelu et al . 2012, 2013). The latter is associated with reduced expression of VEGF, a key promoter of placental vasculogenesis/angiogenesis (Kulandavelu et al .…”