The Role of Placental Growth Factor and Its Primary Receptor, Vegf Receptor 1, in Pulmonary Arterial Hypertension

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Abstract RATIONALE: Pulmonary endothelial cell (EC) dysfunction is a key driver of remodeling in small pulmonary arteries, contributing to pulmonary arterial hypertension (PAH). Although the Vascular Endothelial Growth Factor (VEGF) pathway is essential for regulating ECs, the specific contributions of Placental Growth Factor (PlGF), a member of the VEGF family, and its receptor VEGFR-1 in PAH development remain insufficiently explored. This study aims to delineate the role of PlGF/VEGFR-1 signaling in the progression of PAH in both experimental models and human patients. METHODS: Serum samples from 82 patients with idiopathic PAH (iPAH) and 64 healthy controls were analyzed to measure circulating levels of PlGF and VEGF family proteins via ELISA. Lung tissue samples from control and PAH patients were examined using Western blot and immunofluorescence to assess the expression of VEGFR-1 and VEGFR-2. Mechanistic studies utilized Pl gf knockout (KO) rats, generated by CRISPR/Cas9, exposed to monocrotaline (MCT) or chronic hypoxia (CHx) to assess their susceptibility to pulmonary vascular remodeling. In addition, in vitro studies were performed on human pulmonary microvascular ECs (HPMECs) treated with PlGF siRNA or recombinant PlGF. RESULTS: Patients with iPAH exhibited significantly higher serum levels of PlGF (23.1±1.4 vs. 20.2±1.5 pg/mL, p<0.01) and sVEGFR-1 (133.8±7.2 vs. 113.4±8.0 pg/mL, p<0.01) compared to healthy controls, while levels of VEGF-A and sVEGFR-2 remained unchanged. Notably, elevated PlGF levels correlated with reduced survival (log-rank, PlGF > 27.4 pg/mL, p<0.01). Despite increased circulating PlGF, phosphorylation of VEGFR-1 and VEGFR-2 was diminished, suggesting impaired receptor activity. In animal models, increased PlGF levels were observed alongside decreased VEGFR-1 and VEGFR-2 activity. Pl gf KO rats showed reduced susceptibility to PAH, characterized by lower mean pulmonary arterial pressure (mPAP), total pulmonary vascular resistance (TPVR), Fulton index, and pulmonary arterial muscularization, along with decreased inflammatory markers (CD68, ICAM-1, and VCAM-1). In vitro, PlGF knockdown in HPMECs led to significantly reduced ICAM-1, VCAM-1, and MCP-1 levels, whereas recombinant PlGF treatment increased these markers. CONCLUSION: This study underscores significant alterations in the VEGF pathway in PAH patients, with elevated PlGF levels serving as a predictor of adverse outcomes. The reduced susceptibility to experimental pulmonary hypertension in Plgf KO rats suggests a role for PlGF in PAH mediated by inflammatory processes.

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