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Suppressed Vascular Leakage and Myocardial Edema Improve Outcome From Myocardial Infarction.

ABSTRACT: Aim: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.

SUBMITTER: Li X

PROVIDER: S-EPMC7363985 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Suppressed Vascular Leakage and Myocardial Edema Improve Outcome From Myocardial Infarction.

Li Xiujuan X Redfors Björn B Sáinz-Jaspeado Miguel M Shi Shujing S Martinsson Pernilla P Padhan Narendra N Scharin Täng Margareta M Borén Jan J Levin Malin M Claesson-Welsh Lena L

Frontiers in physiology 20200709

<h4>Aim</h4>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.<h4>Methods and results</h4>VEGFA regulates vascular permeability ...[more]

PMID: 32733273

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Project description:Thiele H, Zeymer U, Neumann FJ, Ferenc M, Olbrich HG, Hausleiter J, Richardt G, Hennersdorf M, Empen K, Fuernau G, Desch S, Eitel I, Hambrecht R, Fuhrmann J, Böhm M, Ebelt H, Schneider S, Schuler G, Werdan K; IABP-SHOCK II Trial Investigators: Intraaortic balloon support for myocardial infarction with cardiogenic shock. N Engl J Med 2012, 367:1287-1296.In the current international guidelines, intra-aortic balloon pump (IABP) counterpulsation is considered a class I treatment for acute myocardial infarction complicated by cardiogenic shock. However, evidence is based mainly on registry data, and there is a paucity of randomized clinical trials.To test the hypothesis that IABP counterpulsation, as compared with the best available medical therapy alone, results in a reduction in mortality among patients with acute myocardial infarction complicated by cardiogenic shock for whom early revascularization is planned.Randomized, prospective, open-label, multicenter trial.Thirty-seven centers in Germany.All adults had acute myocardial infarction complicated by cardiogenic shock and were expected to undergo early revascularization (by means of percutaneous coronary intervention or bypass surgery).After enrollment, 600 patients were randomly assigned to intra-aortic balloon counterpulsation (IABP group, 301 patients) or no IABP counterpulsation (control group, 299 patients).The primary efficacy endpoint is 30-day all-cause mortality.At 30 days, 119 patients in the IABP group (39.7%) and 123 patients in the control group (41.3%) had died (relative risk with IABP, 0.96; 95% confidence interval, 0.79 to 1.17; P=0.69). There were no significant differences in secondary endpoints or in process-of-care measures, including the time to hemodynamic stabilization, the length of stay in the intensive care unit, serum lactate levels, the dose and duration of catecholamine therapy, and renal function.The use of IABP counterpulsation did not significantly reduce 30-day mortality in patients with acute myocardial infarction complicated by cardiogenic shock for whom an early revascularization strategy was planned.

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Suppressed Vascular Leakage and Myocardial Edema Improve Outcome From Myocardial Infarction.

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Suppressed Vascular Leakage and Myocardial Edema Improve Outcome From Myocardial Infarction.

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