Osteopontin Contributes to Uterine Artery Dysfunction During Chronic Hypertensive Pregnancy

Successful pregnancy requires maternal cardiovascular adaptation, including expansion and remodeling of the uterine arteries, to accommodate a progressive rise in uteroplacental blood flow. Chronic maternal hypertension is associated with impaired uterine artery adaptation and adverse pregnancy outcomes, including fetal growth restriction, yet the mechanisms driving these vascular changes remain incompletely understood. Osteopontin, a matricellular protein implicated in vascular pathology in hypertension, is a potential mediator of impaired uterine artery adaptation during pregnancy. In this study, we compared uterine artery remodeling in pregnant normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive stroke-prone rats (SHRSP), a model of chronic hypertension. To investigate the contribution of osteopontin, we characterized an osteopontin-deficient SHRSP strain. Uterine artery hemodynamics were assessed by Doppler ultrasound, arterial structure was evaluated by histology, and molecular profiles were characterized by RNA sequencing. Fetal weight and length were measured at mid and late gestation. We found that, compared with WKY, SHRSP fetuses were smaller and uterine arteries exhibited inward hypertrophic remodeling, including increased wall thickness, reduced lumen area, and an elevated resistance index. SHRSP uterine arteries also showed enrichment of pathways related to inflammation and vascular pathology. Among the most highly upregulated genes was Spp1, which encodes osteopontin. Compared with SHRSP controls, osteopontin-deficient SHRSP had larger uterine artery lumen areas, lower resistance indices, and reduced expression of select inflammation-associated genes. Fetal growth trajectories were also improved. These findings identify osteopontin as a contributor to uterine artery dysfunction in chronic hypertensive pregnancy and demonstrate that osteopontin deficiency improves vascular adaptation and fetal growth.