Preeclampsia-associated changes in umbilical cord stromal VEGFR-2 and EV-mediated in vitro angiogenesis

Preeclampsia (PE) is associated with abnormal placental development, vascular dysfunction, and increased maternal-fetal morbidity. VEGFR-2 is a key mediator of angiogenesis; however, its expression in umbilical cord (UC) stromal compartments, particularly in early-onset (EOPE) and late-onset PE (LOPE), remains insufficiently characterized. We investigated VEGFR-2 expression in distinct UC stromal regions and assessed the angiogenic capacity of human UC-derived multipotent stromal cells (hUC-MSCs) and their extracellular vesicles (EVs).

UC samples from 66 pregnant women were classified as control, EOPE, or LOPE. Cases with intrauterine growth restriction and maternal comorbidities were excluded to minimize potential confounding. Morphometric analysis, immunofluorescence, qRT-PCR, and in vitro HUVEC tube formation assays were performed.

PE cases showed significantly increased umbilical artery lumen area and artery lumen index compared with healthy term controls, with no significant differences between EOPE and LOPE. VEGFR-2 expression showed marked regional heterogeneity, with lower levels in the subepithelial stroma than in intervascular and perivascular regions. Although stromal VEGFR-2 protein levels did not differ significantly between PE and control tissues, median signals in the intervascular and perivascular regions were approximately 15-38% lower in PE groups, accompanied by reduced VEGFR-2 mRNA expression. PE-derived hUC-MSCs also exhibited decreased VEGFR-2 expression and reduced angiogenic capacity, while their EVs showed impaired in vitro HUVEC tube formation activity.

PE is associated with altered UC vascular morphology and impaired VEGFR-2-related angiogenic activity in hUC-MSCs and their EVs. These alterations appear largely independent of whether PE develops early or late in pregnancy.