Dual PEDF and HGF Overexpression: A New Therapy for Pulmonary Hypertension.

PH is a disease characterized by advanced pulmonary vasculature remodeling that is thought to be curable only through lung transplantation. The application of angiogenic HGF is reported to be protective in PH through its anti-vascular remodeling effect, but excessive HGF-mediated immature neovascularization is not conducive to the restoration of pulmonary perfusion due to apparent vascular leakage. As a canonical antiangiogenic molecule, PEDF inhibits angiogenesis and reduces vascular permeability in a variety of diseases. However, the effect of PEDF on HGF-based PH treatment remains to be determined. In this study, monocrotaline-induced PH rats and ECs isolated from rat and human PH lung tissues were used. We assessed PH progression, right cardiac function, and pulmonary perfusion in HGF- and/or PEDF-treated PH rats. Additionally, the receptor and mechanism responsible for the role of PEDF in HGF-based PH therapy were investigated. In this study, we found that HGF and PEDF jointly prevent PH development and improve right cardiac function in PH rats. Moreover, PEDF delivery increases the pulmonary perfusion in PH lungs and inhibits immature angiogenesis and VE-cadherin junction disintegration induced by HGF without affecting the therapeutic inhibition of pulmonary vascular remodeling by HGF. Mechanistically, PEDF targets VEGFR2 and suppresses its phosphorylation at Y951 and Y1175 but not Y1214. Finally, VEGFR2/VEPTP/VE-cadherin complex formation and Akt and Erk1/2 inactivation were observed in rat and human PH lung ECs. Collectively, our data indicate that PEDF additively enhances the efficacy of HGF against PH, which may provide new insights into treatment strategies for clinical PH.