Src blockade stabilizes a Flk/cadherin complex, reducing edema and tissue injury following myocardial infarction.
Ischemia resulting from myocardial infarction (MI) promotes VEGF expression, leading to vascular permeability (VP) and edema, a process that we show here contributes to tissue injury throughout the ventricle. This permeability/edema can be assessed noninvasively by MRI and can be observed at the ultrastructural level as gaps between adjacent endothelial cells. Many of these gaps contain activated platelets adhering to exposed basement membrane, reducing vessel patency. Following MI, genetic or pharmacological blockade of Src preserves endothelial cell barrier function, suppressing VP and infarct volume, providing long-term improvement in cardiac function, fibrosis, and survival. To our surprise, an intravascular injection of VEGF into healthy animals, but not those deficient in Src, induced similar endothelial gaps, VP, platelet plugs, and some myocyte damage. Mechanistically, we show that quiescent blood vessels contain a complex involving Flk, VE-cadherin, and beta-catenin that is transiently disrupted by VEGF injection. Blockade of Src prevents disassociation of this complex with the same kinetics with which it prevents VEGF-mediated VP/edema. These findings define a molecular mechanism to account for the Src requirement in VEGF-mediated permeability and provide a basis for Src inhibition as a therapeutic option for patients with acute MI.
Weis
Sara
S
Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA.
Shintani
Satoshi
S
Weber
Alberto
A
Kirchmair
Rudolf
R
Wood
Malcolm
M
Cravens
Adrianna
A
McSharry
Heather
H
Iwakura
Atsushi
A
Yoon
Young-Sup
YS
Himes
Nathan
N
Burstein
Deborah
D
Doukas
John
J
Soll
Richard
R
Losordo
Douglas
D
Cheresh
David
D
D000818:Animals; D015820:Cadherins / Q000187:drug effects / Q000378:metabolism*; D004487:Edema / Q000378:metabolism*; D009203:Myocardial Infarction / Q000378:metabolism*; D051381:Rats; D042461:Vascular Endothelial Growth Factor A / Q000009:adverse effects; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*
D015820:Cadherins; D042461:Vascular Endothelial Growth Factor A; D019061:src-Family Kinases