Crew, R. C. | bioRxiv Science

bioRxiv2026

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

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 summaryO_LIObesity 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. C_LIO_LIWe 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. C_LIO_LIMothers with obesity carrying a female fetus had elevated uterine vascular resistance in vivo and reduced uterine artery smooth muscle-dependent vasodilator reactivity ex vivo. C_LIO_LIMothers 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. C_LIO_LIThese findings highlight that fetal sex may influence maternal cardiovascular function during obese pregnancy. C_LI

developmental biology↗

bioRxiv2023

An ovine model for investigation of the microenvironment of the male mammary gland

The specific biology of the male breast remains relatively unexplored in spite of the increasing global prevalence of male breast cancer. Delineation of the microenvironment of the male breast is restricted by the low availability of human samples and a lack of characterisation of appropriate animal models. Unlike the mouse, the male ovine gland persists postnatally. We suggest that the male ovine mammary gland constitutes a promising adjunctive model for the male human breast. In this study we evaluate the male ovine mammary gland microenvironment, comparing intact and neutered males. Assessment of the glandular histo-anatomy highlights the resemblance of the male gland to that of the neonatal female sheep and confirms the presence of rudimentary terminal duct lobular units. Irrespective of neutered status, cell proliferation in epithelial and stromal compartments is low in males, and cell proliferation in epithelial cells and in the intralobular stroma is significantly lower than in pubertal female sheep. Between 42% and 72% of the luminal mammary epithelial cells in the male gland express the androgen receptor, and expression is significantly reduced by neutering. Luminal epithelial cells within the intact and neutered male gland also express oestrogen receptor alpha, but minimal progesterone receptor expression is observed. The distrubution of mammary leukocytes within the ducts and stroma is similar in the female mammary gland of sheep and other species. Both macrophages and T lymphocytes are intercalated in the epithelial bilayer and are more abundant in the intralobular stroma than the interlobular stroma, suggesting that they may have a protective immunological function within the vestigial glandular tissue of the male sheep. Mast cells are also observed within the stroma. These cells cluster nearer the glandular tissue and are frequently located adjacent to blood vessels. The abundance of mast cells is significantly higher in intact males compared to neutered males, suggesting that hormone signalling may impact mast cell recruitment. In this study, we demonstrate the utility of the male ovine mammary gland as a model for furthering our knowledge of postnatal male mammary biology.

pathology↗