The acute phase of
myocardial infarction (MI) is accompanied by
edema contributing to tissue damage and disease outcome. Here, we aimed to identify the mechanism whereby
vascular endothelial growth factor (
VEGF)-A induces myocardial
edema in the acute phase of MI to eventually promote development of
therapeutics to specifically suppress VEGFA-regulated vascular permeability while preserving collateral vessel formation.
METHODS AND RESULTS: VEGFA regulates vascular permeability and
edema by activation of
VEGF receptor-2 (VEGFR2), leading to induction of several signaling pathways including the cytoplasmic
tyrosine kinase c-Src. The activated c-Src in turn phosphorylates vascular endothelial (
VE)-cadherin, leading to dissociation of endothelial adherens junctions. A particular
tyrosine at position 949 in mouse VEGFR2 has been shown to be required for activation of c-Src. Wild-type mice and mice with
phenylalanine replacing
tyrosine (Y) 949 in VEGFR2 (Vegfr2 Y949F/Y949F ) were challenged with MI through permanent
ligation of the left anterior descending coronary artery. The
infarct size was similar in wild-type and mutant mice, but left ventricular wall
edema and
fibrinogen deposition, indicative of vascular leakage, were reduced in the Vegfr2 Y949F/Y949F strain. When challenged with large
infarcts, the Vegfr2 Y949F/Y949F mice survived significantly better than the wild-type strain. Moreover, neutrophil infiltration and levels of
myeloperoxidase were low in the infarcted Vegfr2 Y949F/Y949F hearts, correlating with improved survival. In vivo
tyrosine phosphorylation of
VE-cadherin at Y685, implicated in regulation of vascular permeability, was induced by circulating VEGFA in the wild-type but remained at baseline levels in the Vegfr2 Y949F/Y949F hearts.
CONCLUSION: Suppression of VEGFA/VEGFR2-regulated vascular permeability leads to diminished
edema without affecting vascular density correlating with improved myocardial parameters and survival after MI.