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

Research output: Contribution to journalArticle

261 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)885-894
Number of pages10
JournalJournal of Clinical Investigation
Volume113
Issue number6
DOIs
Publication statusPublished - 2004 Mar 1

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Cadherins
Vascular Endothelial Growth Factor A
Capillary Permeability
Edema
Myocardial Infarction
Wounds and Injuries
Permeability
Blood Platelets
Endothelial Cells
Catenins
Injections
Basement Membrane
Muscle Cells
Blood Vessels
Fibrosis
Ischemia
Pharmacology
Survival

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Weis, Sara ; Shintani, Satoshi ; Weber, Alberto ; Kirchmair, Rudolf ; Wood, Malcolm ; Cravens, Adrianna ; McSharry, Heather ; Iwakura, Atsushi ; Yoon, Young Sup ; Himes, Nathan ; Burstein, Deborah ; Doukas, John ; Soll, Richard ; Losordo, Douglas ; Cheresh, David. / Src blockade stabilizes a Flk/cadherin complex, reducing edema and tissue injury following myocardial infarction. In: Journal of Clinical Investigation. 2004 ; Vol. 113, No. 6. pp. 885-894.
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Weis, S, Shintani, S, Weber, A, Kirchmair, R, Wood, M, Cravens, A, McSharry, H, Iwakura, A, Yoon, YS, Himes, N, Burstein, D, Doukas, J, Soll, R, Losordo, D & Cheresh, D 2004, 'Src blockade stabilizes a Flk/cadherin complex, reducing edema and tissue injury following myocardial infarction', Journal of Clinical Investigation, vol. 113, no. 6, pp. 885-894. https://doi.org/10.1172/JCI200420702

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

In: Journal of Clinical Investigation, Vol. 113, No. 6, 01.03.2004, p. 885-894.

Research output: Contribution to journalArticle

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T1 - Src blockade stabilizes a Flk/cadherin complex, reducing edema and tissue injury following myocardial infarction

AU - Weis, Sara

AU - Shintani, Satoshi

AU - Weber, Alberto

AU - Kirchmair, Rudolf

AU - Wood, Malcolm

AU - Cravens, Adrianna

AU - McSharry, Heather

AU - Iwakura, Atsushi

AU - Yoon, Young Sup

AU - Himes, Nathan

AU - Burstein, Deborah

AU - Doukas, John

AU - Soll, Richard

AU - Losordo, Douglas

AU - Cheresh, David

PY - 2004/3/1

Y1 - 2004/3/1

N2 - 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.

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