Glycoside fraction from pear seed functionally antagonizes sFLT-1 and restores angiogenic signaling in preeclampsia

Abstract

Preeclampsia is characterized by endothelial dysfunction and angiogenic imbalance driven, in part, by excess soluble fms-like tyrosine kinase-1 (sFLT-1). Building on previous findings demonstrating vascular modulatory effects of cardiac and quercetin glycosides from Dacryodes edulis seeds during L-NAME-induced vascular perturbation, we investigated whether pear seed glycosides (PSG) modulate sFLT-1-mediated endothelial injury in preeclampsia. Endothelial, preclinical, biophysical, pharmacodynamic, and exploratory clinical approaches were integrated to evaluate PSG activity. TGFβ-stimulated HUVECs, an L-NAME-induced rat model of preeclampsia, orthogonal binding assays (SPR/BLI and MST), ligand competition assays, and a multicenter double-blind phase 1-2a exploratory clinical trial were employed. PSG reduced endothelial migration and suppressed αSMA, TNFα, and fibronectin expression in stimulated HUVECs. In preeclamptic rats, PSG attenuated systolic and diastolic blood pressure elevation, reduced inflammatory and cardiovascular injury markers, restored VEGF and placental growth factor (PlGF), and reduced circulating sFLT-1 and the sFLT-1/PlGF ratio. Bioactivity-guided fractionation identified glycosides as the principal active fraction and improved mean birth weight from 2.7 g in untreated preeclamptic dams to 3.5 g, approaching normotensive controls (3.7 g). Orthogonal SPR/BLI and MST assays demonstrated concentration-dependent PSG-sFLT-1 interactions, while competitive ELISA and BLI assays showed inhibition of sFLT-1-mediated sequestration of VEGF and PlGF. PSG additionally restored VEGFR2/KDR, AKT, and ERK signaling in sFLT-1-exposed endothelial cells. In the exploratory clinical trial, 83 participants were randomized following screening of 125 women, with approximately 80% completing follow-up. PSG administration alongside standard care did not reveal major treatment-emergent safety concerns. These findings support further investigation of PSG as a candidate adjunctive strategy targeting angiogenic dysfunction in preeclampsia.