Src blockade stabilizes a Flk/cadherin complex, reducing edema and tissue injury following myocardial infarction
Sara Weis, … , Douglas Losordo, David Cheresh
Sara Weis, … , Douglas Losordo, David Cheresh
Published March 15, 2004
Citation Information: J Clin Invest. 2004;113(6):885-894. https://doi.org/10.1172/JCI20702.
View: Text | PDF
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

×

Figure 1

Options: View larger image (or click on image) Download as PowerPoint
Src blockade protects following myocardial infarction. (A) pp60Src–/– mi...
Src blockade protects following myocardial infarction. (A) pp60Src–/– mice have significantly reduced myocardial water content and infarct size 24 hours after MI. (B) MRI T2 maps overlaid on gradient echo images in rats treated with vehicle or the PP1 Src inhibitor. Scale at right indicates T2 values from red (lower T2) to blue (higher T2). T2 values greater than 40 milliseconds were used as an index of edema, and representative images reveal reduced volume containing T2 values greater than 40 milliseconds 24 hours following MI in PP1-treated rats. Graph shows significant differences of the percentage of LVs with T2 values greater than 40 milliseconds between vehicle- and SKI-606 treated rats. (C) Treatment with a Src inhibitor results in significant and dose-dependent decreases in myocardial water content and infarct size after MI. Single-dose treatment with a Src inhibitor was optimally effective in reducing infarct size when administered 45 minutes after LAD ligation and still reduced infarct size significantly when administered up to 6 hours after infarct. (D) Src inhibition reduces infarct size and preserves function following transient ischemia and reperfusion. All panels represent the Src inhibitor PP1, except for B, as noted, and D, right panel, in which the Src inhibitor SKI-606 was used. *P < 0.05; **P < 0.001.