Abstract
AimThe 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 ResultsVEGFA 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 (Vegfr2Y949F/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 Vegfr2Y949F/Y949F strain. When challenged with large infarcts, the Vegfr2Y949F/Y949F mice survived significantly better than the wild-type strain. Moreover, neutrophil infiltration and levels of myeloperoxidase were low in the infarcted Vegfr2Y949F/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 Vegfr2Y949F/Y949F hearts.ConclusionSuppression of VEGFA/VEGFR2-regulated vascular permeability leads to diminished edema without affecting vascular density correlating with improved myocardial parameters and survival after MI.
Highlights
Vascular endothelial growth factor-A (VEGFA) plays a protective role in ischemic heart disease and myocardial infarction (MI) by inducing angiogenesis (Kajdaniuk et al, 2011)
Suppression of VEGFA/VEGF receptor-2 (VEGFR2)-regulated vascular permeability leads to diminished edema without affecting vascular density correlating with improved myocardial parameters and survival after MI
We used mice in which VEGFR2 Y949 is replaced by F949 (Vegfr2Y949F/Y949F), and where adherens junctions in different vascular beds remain stable when exposed to VEGFA (Li et al, 2016; Smith et al, 2020)
Summary
Vascular endothelial growth factor-A (VEGFA) plays a protective role in ischemic heart disease and myocardial infarction (MI) by inducing angiogenesis (Kajdaniuk et al, 2011). Phosphorylated (p) Y949 in VEGFR2 mediates c-Src activation at EC junctions (Sun et al, 2012; Li et al, 2016), and loss of pY949 signaling in Vegfr2Y949F/Y949F mice results in reduced vascular leakage in response to VEGFA administration, in the dermal and tracheal vasculature (Li et al, 2016). Vascular permeability and edema are lower in Vegfr2Y949F/Y949F mice compared to wild-type, after challenge with GL261 glioma, B16F10 melanoma and RipTag neuroendocrine cancer. The enforced vascular barrier in the Vegfr2Y949F/Y949F mice correlates with decreased metastatic spread from melanoma and neuroendocrine cancer in mice (Li et al, 2016)
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