Maternal cardiometabolic dysfunction and fetal sex-specific alterations to uterine vascular reactivity in an ovine model of diet-induced obesity during pregnancy

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Abstract Obesity during pregnancy is at pandemic proportions and predisposes women to pre- and postnatal cardiovascular dysfunction. The mechanisms underlying this maternal cardiovascular vulnerability remain unclear, partly due to a lack of translatable models capable of longitudinal in vivo cardiovascular monitoring. Here, we characterise a novel ovine model of maternal diet-induced obesity during pregnancy. Ewes were fed a control (CON) or obesogenic (OB; ad libitum concentrates) diet for 60 days pre-pregnancy and throughout gestation. Pregnant ewes were surgically instrumented with vascular catheters and Transonic flow probes using the wireless CamDAS system, which measured maternal cardiovascular function near term in free-moving ewes. Uterine artery vasoreactivity was assessed ex vivo by in vitro wire myography. OB ewes entered pregnancy 30% heavier than controls ( P <0.003) and were hyperglycaemic, hyperinsulinemic, and hyperlipidaemic during pregnancy, relative to CON ewes (all P <0.05). OB ewes had elevated haematocrit and haemoglobin across pregnancy, and were hypertensive near term, with an increase in basal femoral artery blood flow, and elevated peripheral oxygen and glucose delivery (all P <0.05). OB mothers carrying a female fetus showed increased uterine artery vascular resistance in vivo ( P <0.005) and reduced smooth muscle-dependent vasorelaxation ex vivo ( P <0.05) relative to CON. Conversely, OB mothers carrying a male fetus showed greater NO-independent mechanisms mediating the uterine vasodilator response to methacholine ex vivo ( P <0.001). Collectively, this study characterises a robust model of maternal obesity during pregnancy that offers clinical translational potential and highlights fetal sex-specific changes to uterine artery function. Key points summary Obesity during pregnancy is increasingly common and predisposes women to cardiovascular dysfunction during pregnancy and long after birth, but the specific mechanisms underlying this remain unclear. We developed a novel ovine model of diet-induced obesity during pregnancy that displays maternal hypertension, elevated haemoglobin, metabolic dysfunction and alterations in uterine and peripheral blood flow and nutrient delivery near term. Mothers with obesity carrying a female fetus had elevated uterine vascular resistance in vivo and reduced uterine artery smooth muscle-dependent vasodilator reactivity ex vivo . Mothers with obesity carrying a male fetus showed no effect on uterine vascular resistance in vivo , but greater NO-independent mechanisms mediating the uterine vasodilator response to methacholine ex vivo . These findings highlight that fetal sex may influence maternal cardiovascular function during obese pregnancy.

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