Impaired Uterine Artery Remodeling and Uterine Artery Perivascular Adipose Tissue Microenvironment in a Mouse Model of Obesity and Superimposed Preeclampsia

Impaired uteroplacental vascular remodeling and placental hypoxia are key pathophysiological features of preeclampsia, a leading hypertensive disorder of pregnancy markedly influenced by maternal obesity. Uterine arteries undergo significant remodeling in healthy pregnancies. Yet, increased uterine artery resistance may be detected as early as 11-14 weeks of gestation in women who later develop preeclampsia. Perivascular adipose tissue (PVAT) surrounds most blood vessels, supports vascular homeostasis, and may modulate vascular remodeling. Importantly, PVAT may become proinflammatory and profibrotic in obesity, exacerbating vascular dysfunction. While uterine artery PVAT (utPVAT) has been proposed to have a vasoactive role in healthy pregnancies, the role of utPVAT in pregnancies affected by obesity and preeclampsia remains unknown. Using the spontaneously obese and preeclamptic-like Blood Pressure High Subline 5 (BPH/5) mouse, we aimed to elucidate remodeling of the upstream uterine arteries and the molecular-immune profile of their surrounding utPVAT in the context of obesity and preeclampsia. We hypothesized that uterine arteries from BPH/5 females would display impaired outward hypertrophic remodeling that is characteristic of healthy pregnancies. Additionally, we hypothesized that the expanded BPH/5 utPVAT would present signs of hypoxia and inflammation. Uterine arteries and surrounding utPVAT were collected from adult (8–12-week-old) non-pregnant (NP) and late-gestation (e18.5) BPH/5 and control Blood Pressure Normal Subline 3 (BPN/3) females. Day of copulation was defined as embryonic day (e) 0.5. Uterine artery diameter and wall thickness were quantified histologically using paraformaldehyde-fixed samples. UtPVAT immunophenotyping was performed by flow cytometry and utPVAT Hypoxia-inducible factor 1 alpha (Hif1a) and Vascular endothelial growth factor alpha (Vegfa) gene expression were assessed using RT-qPCR. Two-way ANOVA and post-hoc Tukey’s tests were used for comparisons (GraphPad Prism). In BPN/3 females, uterine artery lumen and media thickness were greater at e18.5 compared to NP (p< 0.05). Conversely, uterine artery media thickness and lumen diameter were comparable between NP and e18.5 BPH/5 females (p >0.05). BPH/5 females had greater utPVAT mass than controls pre-pregnancy and during late gestation (p< 0.05). In UtPVAT from NP and e18.5 BPH/5 females, macrophages comprised a greater proportion of the stromal vascular fraction, whereas dendritic cells and eosinophils were correspondingly reduced in comparison to reproductive status-matched BPN/3 (p< 0.05). Hif1a and Vegfa were not different between e18.5 BPH/5 and BPN/3 utPVAT (p >0.05). In conclusion, BPN/3 displayed histological evidence of uncomplicated outward hypertrophic uterine artery remodeling at late gestation. Alternatively, similar media thickness and lumen diameter between uterine arteries of NP and e18.5 BPH/5 mice are suggestive of impaired remodeling. BPH/5 mice also displayed utPVAT expansion and appear proinflammatory, suggesting a disrupted microenvironment that may contribute to impaired vascular remodeling. Although Hif1a and Vegfa gene expression were unchanged in e18.5 BPH/5 and BPN/3 utPVAT, further studies of BPH/5 utPVAT hypoxia may be warranted. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.