Placental Growth Factor Promotes Endothelial Activation and Inflammatory Remodelling in Pulmonary Hypertension
My Ngoc Ha, Raphaël Thuillet, Mina Ottaviani, Corinne Normand, Fabien Robert, Maxime Surbier, Olivier Sitbon, Marc Humbert, Athénaïs Boucly, Laurent Savale, Deborah J Gorth, Vanessa Petit, Ly Tu, Christophe GuignabertAbstract
Aims
Pulmonary arterial hypertension (PAH) is a progressive cardiopulmonary disorder marked by pulmonary vascular remodelling and vessel loss, paradoxically occurring despite high VEGF signaling. While VEGF/VEGFR pathways are implicated in disease pathogenesis, their role in endothelial and immune cell crosstalk remains poorly understood. Placental growth factor (PlGF), a VEGF family member that selectively binds VEGFR-1, exerts pro-inflammatory effects in other pathological contexts, but its contribution to PAH pathophysiology is unclear. This study explored the contribution of PlGF to endothelial activation and immune-mediated vascular remodelling in PAH.
Methods and Results
Serum levels of PlGF, VEGF-A, soluble VEGFR-1 (sVEGFR-1), and soluble VEGFR-2 (sVEGFR-2) were measured in 80 treatment-naïve PAH patients from the EFORT cohort and in healthy controls. Their association with survival was then assessed. VEGFR-1 expression was evaluated in human PAH lung tissue. The functional role of PlGF was investigated in Plgf-/- rats exposed to chronic hypoxia or monocrotaline, and in mechanistic studies using primary human pulmonary endothelial cells and monocyte-derived macrophages.
Circulating PlGF and sVEGFR-1 were elevated in PAH and associated with worse survival. VEGFR-1 expression was increased in PAH lung endothelium. Genetic deletion of Plgf protected rats from experimental pulmonary hypertension, leading to reduced pulmonary pressures, right ventricular hypertrophy, and vascular remodelling. PlGF deficiency reduced endothelial ICAM-1/VCAM-1 expression, macrophage infiltration, and pro-inflammatory cytokine production (CCL5/RANTES, osteoprotegerin, and LIX/CXCL5). In vitro, PlGF induced endothelial adhesion molecule expression and promoted macrophage polarization toward a pro-remodelling M2-like phenotype.
Conclusions
PlGF is upregulated in PAH, its concentration predicts adverse outcomes, and it actively drives vascular remodelling by coupling endothelial activation to immune dysregulation. These findings establish PlGF as both a prognostic biomarker and a promising therapeutic target for PAH.