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Am J Physiol Heart Circ Physiol (September 19, 2005). doi:10.1152/ajpheart.00457.2005
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Submitted on May 6, 2005
Accepted on August 19, 2005

Matrix Metalloproteinase-9 Gene Deletion Facilitates Angiogenesis Following Myocardial Infarction

Merry L Lindsey1*, G. Patricia Escobar1, L. W. Dobrucki2, Danielle K Goshorn1, Shenikqua Bouges1, Joseph T Mingoia1, David M McClister, Jr.1, Haili Su2, Joseph Gannon3, Catherine MacGillivray3, Richard T Lee3, Albert J Sinusas2, and Francis G Spinale4

1 Cardiothoracic Surgery Research, Medical University of South Carolina, Charleston, SC, USA
2 Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT, USA
3 Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
4 Cardiothoracic Surgery Research, Medical University of South Carolina, Charleston, SC, USA; Ralph A. Johnson Veterans Administration Medical Center, Charleston, SC, USA

* To whom correspondence should be addressed. E-mail: lindseml{at}musc.edu.

Matrix metalloproteinases (MMPs) are postulated to be necessary for neovascularization during wound healing. MMP-9 deletion alters remodeling post-myocardial infarction (MI), but whether and to what degree MMP-9 affects neovascularization post-MI is unknown. Neovascularization was evaluated in wild-type (WT;n=63) and MMP-9-null mice (n=55) at 7-days post-MI. Despite similar infarct sizes, MMP-9 deletion improved left ventricular function as evaluated by hemodynamic analysis. Blood vessel quantity and quality was evaluated by three independent studies. First, vessel density was increased in the infarct of MMP-9-null mice compared with WT, as quantified by Griffonia (Bandeiraea) Simplicifolia Lectin-I (GSL-I) immunohistochemistry. Second, pre-existing vessels, stained in vivo with FITC-labeled GSL-I pre-MI, were present in the viable but not MI region. Third, a technetium-99m labeled peptide (NC100692), which selectively binds to activated {alpha}v{beta}3 integrin in angiogenic vessels, was injected into post-MI mice. Relative NC100692 activity in myocardial segments with diminished perfusion (0-40% non-ischemic) was higher in MMP-9-null than WT mice (383±162% vs. 250±118%, respectively;p=0.002). The unique finding of this study was that MMP-9 deletion stimulated, rather than impaired, neovascularization in remodeling myocardium. Thus, targeted strategies to inhibit MMP-9 early post-MI will likely not impair the angiogenic response.




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