PEDF inhibits VEGF-induced vascular leakage through binding to VEGFR2 in acute myocardial infarction

Abstract

Pigment epithelium-derived factor (PEDF) could bind to vascular endothelial growth factor receptor 2 (VEGFR2) and inhibit its activation induced by VEGF. But how PEDF affects VEGFR2 pathway is still poorly understood. In this study, we elucidated the precise mechanism underlying the interaction between PEDF and VEGFR2, and subsequently corroborated our findings using a rat AMI model. PEDF prevented endocytosis of VE-cadherin induced by hypoxia, thereby protecting the endothelium integrity. A three-dimensional model of the VEGFR2-PEDF complex was constructed by protein-protein docking method. The results showed that the VEGFR2-PEDF complex was stable during the simulation. Hydrogen bonds, binding energy and binding modes were analyzed during molecular dynamics simulations, which indicated that hydrogen bonds and hydrophobic interactions were important for the recognition of VEGFR2 with PEDF. In addition, the results from exudation of fibrinogen suggested that PEDF inhibits vascular leakage in acute myocardial infarction and confirmed the critical role of key amino acids in the regulation of endothelial cell permeability. This observation is also supported by echocardiography studies showing that the 34mer peptide sustained cardiac function during acute myocardial infarction. Besides, PEDF and 34mer could inhibit the aggregation of myofiber in the heart and promoted the formation of a dense cell layer in cardiomyocytes, which suggested that PEDF and 34mer peptide protect against AMI-induced cardiac dysfunction. These results suggest that PEDF inhibits the phosphorylation of downstream proteins, thereby preventing vascular leakage, which provides a new therapeutic direction for the treatment of acute myocardial infarction. Communicated by Ramaswamy H. Sarma