Src blockade stabilizes a Flk/cadherin complex, reducing edema and tissue injury following myocardial infarction.

Publication/Presentation Date

3-1-2004

Abstract

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.

Volume

113

Issue

6

First Page

885

Last Page

894

ISSN

0021-9738

Disciplines

Diagnosis | Medicine and Health Sciences | Other Analytical, Diagnostic and Therapeutic Techniques and Equipment | Radiology

PubMedID

15067321

Department(s)

Department of Radiology and Diagnostic Medical Imaging

Document Type

Article

Link to Full Text

Share

COinS