Src blockade stabilizes a Flk/cadherin complex, reducing edema and tissue injury following myocardial infarction
Sara Weis, Satoshi Shintani, Alberto Weber, Rudolf Kirchmair, Malcolm Wood, Adrianna Cravens, Heather McSharry, Atsushi Iwakura, Young-sup Yoon, Nathan Himes, Deborah Burstein, John Doukas, Richard Soll, Douglas Losordo, David Cheresh
Sara Weis, Satoshi Shintani, Alberto Weber, Rudolf Kirchmair, Malcolm Wood, Adrianna Cravens, Heather McSharry, Atsushi Iwakura, Young-sup Yoon, Nathan Himes, Deborah Burstein, John Doukas, Richard Soll, Douglas Losordo, David Cheresh
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Article Cardiology

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

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 β-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.

Authors

Sara Weis, Satoshi Shintani, Alberto Weber, Rudolf Kirchmair, Malcolm Wood, Adrianna Cravens, Heather McSharry, Atsushi Iwakura, Young-sup Yoon, Nathan Himes, Deborah Burstein, John Doukas, Richard Soll, Douglas Losordo, David Cheresh

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Sequence of cellular and molecular events following MI. The link between...
Sequence of cellular and molecular events following MI. The link between edema and poor clinical outcome following myocardial infarction has remained poorly understood. We propose a pathway in which hypoxia-driven VEGF expression following MI leads to edema and cardiac damage. Upon VEGF stimulation, Src activity is required for the disruption of a preformed Flk-cadherin-catenin complex, which loosens EC-cell contacts and permits extravasation of serum and blood cells. The resulting edema and inflammation increase interstitial pressure, which reduces local blood flow and causes further hypoxia. Endothelial gaps also expose basal lamina, attracting platelets that adhere, become activated, and could release VEGF locally. Platelet aggregates form microthrombi that can limit blood flow through smaller vessels, thereby increasing hypoxia and contributing to the expansion of cardiac damage and infarcted tissue that is associated with poor clinical outcome. Src blockade delivered within the first few hours following vessel occlusion could prevent VEGF-induced dissociation of the Flk-cadherin-catenin complex and preserve endothelial barrier integrity, thereby eliminating the further damage and infarct expansion beyond the initial ischemic boundary.