Osteopontin Mediates Uterine Artery Dysfunction in Hypertensive Pregnancy

Abstract

BackgroundSuccessful pregnancy requires substantial maternal cardiovascular adaptation, including expansion and remodelling of the uterine arteries to support increased nutrient flow to the fetus. Hypertension is associated with impaired uterine artery remodelling and increased risk of fetal growth restriction and other adverse outcomes, yet the mechanisms driving vascular dysfunction in hypertensive pregnancy remain incompletely understood. Osteopontin, a matricellular protein, is implicated in vascular pathology in hypertension, positioning it as a candidate mediator of impaired uterine artery adaptation during hypertensive pregnancy. MethodsUterine artery remodelling was compared between pregnant normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive stroke-prone rats (SHRSP), a model of chronic hypertension. To determine the role of osteopontin in this process, an osteopontin-deficient SHRSP strain was characterized. Uterine artery blood flow was assessed by Doppler ultrasound, arterial structure was evaluated by histology, and molecular differences were identified by RNA sequencing. Fetal weight and length were measured at mid and late gestation. ResultsCompared with WKY, SHRSP fetuses were smaller, and uterine arteries exhibited inward hypertrophic remodelling, characterized by increased wall thickness, reduced lumen area, and elevated resistance index. SHRSP uterine arteries also showed increased expression of inflammatory and vascular pathology-associated genes, including osteopontin. In osteopontin-deficient SHRSP, uterine arteries had larger lumen areas, decreased resistance index, and reduced expression of inflammation-associated genes. Fetal growth was also improved in osteopontin-deficient SHRSP pregnancies. ConclusionsThese findings identify osteopontin as a contributor to impaired uterine artery adaptation and suggest that reduced osteopontin may improve vascular remodelling and fetal growth in hypertensive pregnancies.