Uteroplacental insufficiency programs regional vascular dysfunction and alters arterial stiffness in female offspring

Abstract

Intrauterine growth restriction caused by uteroplacental insufficiency increases the risk of cardiovascular disease in adulthood. Vascular mechanisms in female offspring are poorly understood. The aim of this study was to investigate the effects of uteroplacental insufficiency on blood pressure, vascular reactivity and arterial stiffness in four vascular beds in female offspring born growth restricted. Uteroplacental insufficiency was induced on day 18 of gestation in Wistar Kyoto rats by bilateral uterine vessel ligation (Restricted) or sham surgery (Controls). Wire and pressure myography were used to test endothelial and smooth muscle function, and passive mechanical wall properties, respectively, in uterine, mesenteric, renal and femoral arteries of 18-month-old female offspring. Collagen and elastin fibres were quantified using circular crossed-polarized light microscopy and quantitative real time polymerase chain reaction. Restricted female offspring were born 10-15% smaller. Restricted females were normotensive, had plasma triglycerides 2-fold elevated and had uterine endothelial dysfunction, attributed to a 23% reduction in the maximal relaxation produced by endothelium-derived hyperpolarizing factor. Uterine artery stiffness was increased, with an augmented proportion of thick and decreased proportion of thin collagen fibres. Vascular reactivity and mechanical wall properties were preserved in mesenteric, renal and femoral arteries in growth restricted females. Female offspring born growth restricted have selective uterine artery endothelial dysfunction and increased wall stiffness. The preserved vascular function in other arteries may explain the lack of hypertension in these females. The uterine artery specific dysfunction has potential implications for impaired pregnancy adaptations and a compromised intrauterine environment of the next generation.

Alterations in maternal and fetal heart functions accompany failed spiral arterial remodeling in pregnant mice

“…1,2 In humans, inadequate modification of decidual and myometrial SA is often accompanied by preeclampsia (PE) and/or intrauterine growth restriction (IUGR). 3,4 SA remodeling is progressive and involves loss of vascular smooth muscle coat and elastic lamina, mural invasion by trophoblast cells that deposit nonvasoactive fibrinoid and transient replacement of vascular endothelial cells by intravascular trophoblast. 2,5 In humans, SA remodeling normally occurs during first and second trimester with ~2/3 of these vessels dilating 5-10 fold.…”

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Abstract OBJECTIVE-Our goal was to define mechanisms that protect murine pregnancies deficient in spiral arterial (SA) remodeling from hypertension, hypoxia and intra-uterine growth restriction.STUDY DESIGN-Micro-ultrasound analyses were conducted on virgin, gestation day (gd) 2,4,7,9,10,12,14,16,18 and postpartum BALB/c (WT) mice and BALB/c-Rag2 −/− /Il2rg −/− mice, an immunodeficient strain lacking SA remodeling.

RESULTS-Rag2−/− /Il2rg −/− dams had normal SA flow velocities, greatly elevated uterine artery flow velocities between gd10-16 and smaller areas of placental flow from gd14 to term than controls. Maternal heart weight and output increased transiently.

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“…STUDY DESIGN-Micro-ultrasound analyses were conducted on virgin, gestation day (gd) 2,4,7,9,10,12,14,16,18 and postpartum BALB/c (WT) mice and BALB/c-Rag2 −/− /Il2rg −/− mice, an immunodeficient strain lacking SA remodeling.…”

Low female birth weight and advanced maternal age programme alterations in next-generation blastocyst development

“…We have also previously reported no alterations in F2 litter size, which is indicative of maintenance of pregnancy by F1 growth-restricted females (Gallo et al 2012b). While these experiments demonstrate that there are no differences in birth weight of F2 restricted offspring, cellular deficits and programming of metabolic disease and hypertension occur in a sex-specific manner in F2 offspring , Moritz et al 2009, Mazzuca et al 2010, Gallo et al 2012b. Importantly, we have previously demonstrated loss of glucose tolerance during late gestation in F1 growth-restricted mothers at 4 months of age (Mazzuca et al 2010, Gallo et al 2012b.…”

“…Both F1 male and female offspring have organ deficits, but only F1 male offspring develop hypertension and metabolic dysfunction in adult life (Wadley et al 2008, Moritz et al 2009). During late gestation, F1 female growth-restricted offspring become glucose intolerant, develop glomerular hypertrophy and have modifications in uterine artery function (Mazzuca et al 2010, Gallo et al 2012b. Alterations in the intrauterine nutrient environment caused by glucose intolerance may compromise F2 embryonic and fetal development, and therefore programme disease development in that generation, particularly affecting germ cell development.…”