Abstract
BACKGROUND: Preeclampsia (PE) is a major hypertensive disorder of pregnancy rooted in defective placental vascular remodeling. Osteopontin (SPP1) is implicated in placental development, but its role in orchestrating the critical paracrine dialogue between trophoblasts and endothelial cells remains undefined. METHODS: Placental SPP1 expression and microvessel density (MVD) were analyzed in PE and control pregnancies. An in vitro hypoxia-reoxygenation (H/R) model with SPP1 manipulation in HTR-8/SVneo trophoblasts was used to assess cell functions. Trophoblast-endothelial communication was evaluated via a Transwell co-culture system with HUVECs. Key signaling (integrin αVβ3-PI3K/Akt/FAK) and the MMP-9/TIMP-1 balance were examined. Serum SPP1, sFlt-1, and PlGF were measured. In vivo, we established an N-nitro-L-arginine methyl ester (L-NAME)-induced PE rat model, and evaluated the therapeutic effect of recombinant SPP1 supplementation on PE-like phenotypes, placental vascular remodeling and the underlying signaling changes. RESULTS: SPP1 was downregulated in PE placentas and positively correlated with MVD. H/R reduced SPP1 secretion, impairing trophoblast invasion/proliferation and suppressing endothelial tube formation via paracrine signaling. Mechanistically, trophoblast-derived SPP1 promoted angiogenesis by activating endothelial integrin αVβ3-PI3K/Akt/FAK signaling and restoring the MMP-9/TIMP-1 balance. Downregulated SPP1 disrupts EVT-endothelial paracrine signaling required for spiral artery‑like remodeling. In vivo, SPP1 supplementation ameliorated PE phenotypes, restored placental vascular density, and reversed signaling defects in a rat model. Clinically, serum SPP1 levels were reduced in PE and inversely correlated with the sFlt-1/PlGF ratio and disease severity, highlighting its predictive value. CONCLUSION: SPP1 is a central paracrine mediator of trophoblast-endothelial crosstalk, and its hypoxia-induced reduced expression drives vascular dysfunction in PE via the integrin αVβ3-PI3K/Akt-MMP-9/TIMP-1 axis. Our findings nominate SPP1 as both a promising biomarker and a potential therapeutic target for PE.