VEGF, flk-1, and flt-1 expression in a rat myocardial infarction model of angiogenesis

Abstract

Vascular endothelial growth factor (VEGF) is an endothelial cell mitogen that is thought to function by interacting with two high-affinity receptors, flk-1 and flt-1. In an adult heart, angiogenesis can occur in a number of pathological conditions, including atherosclerosis, hypertrophy, and infarction. To determine the role played by VEGF, flk-1, and flt-1 in this process in vivo, we studied the expression of the growth factor and its receptors in a rat infarct model. After an acute myocardial infarction, we observed an initial rapid (1h) rise in VEGF (275%), flk-1 (375%), and flt-1 (400%) mRNA expression throughout the entire heart. Initial diffuse induction of VEGF, flk-1, and flt-1 expression in the left ventricle was later replaced by an increase predominantly limited to perimyocardial infarction area where angiogenesis was taking place. In situ hybridization showed at 6 h after infarction, viable myocytes adjacent to the infarct zone expressed markedly increased amounts of VEGF. At both 6 and 24 h, microvessels at the infarct edge overexpressed both flk-1 and flt-1 mRNAs; at 3 and 7 days new vessels infiltrating the infarct also overexpressed both receptors and continued for as late as 6 wk. In summary, acute myocardial infarction is accompanied by rapid and prolonged increase in expression of VEGF and its receptors with characteristic spatial and temporal kinetic. These findings suggest that the VEGF/VEGF receptor system plays an important role in the angiogenesis and stromal deposition associated with myocardial infarction.