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This Article Full Text Full Text (PDF) All Versions of this Article: 297/5/R1503    most recent 00227.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Zisa, D. Articles by Lee, T. PubMed PubMed Citation Articles by Zisa, D. Articles by Lee, T.

Articles

Intramuscular VEGF repairs the failing heart: role of host-derived growth factors and mobilization of progenitor cells

Department of Biochemistry and Center for Research in Cardiovascular Medicine, University at Buffalo, Buffalo, New York

Submitted April 24, 2009 ; accepted in final form September 9, 2009

Skeletal muscle produces a myriad of mitogenic factors possessing cardiovascular regulatory effects that can be explored for cardiac repair. Given the reported findings that VEGF may modulate muscle regeneration, we investigated the therapeutic effects of chronic injections of low doses of human recombinant VEGF-A₁₆₅ (0.1–1 µg/kg) into the dystrophic hamstring muscle in a hereditary hamster model of heart failure and muscular dystrophy. In vitro, VEGF stimulated proliferation, migration, and growth factor production of cultured C2C12 skeletal myocytes. VEGF also induced production of HGF, IGF2, and VEGF by skeletal muscle. Analysis of skeletal muscle revealed an increase in myocyte nuclear [531 ± 12 VEGF 1 µg/kg vs. 364 ± 19 for saline (number/mm²) saline] and capillary [591 ± 80 VEGF 1 µg/kg vs. 342 ± 21 for saline (number/mm²)] densities. Skeletal muscle analysis revealed an increase in Ki67⁺ nuclei in the VEGF 1 µg/kg group compared with saline. In addition, VEGF mobilized c-kit⁺, CD31⁺, and CXCR4⁺ progenitor cells. Mobilization of progenitor cells was consistent with higher SDF-1 concentrations found in hamstring, plasma, and heart in the VEGF group. Echocardiogram analysis demonstrated improvement in left ventricular ejection fraction (0.60 ± 0.02 VEGF 1 µg/kg vs. 0.45 ± 0.01 mm for saline) and an attenuation in ventricular dilation [5.59 ± 0.12 VEGF 1 µg/kg vs. 6.03 ± 0.09 for saline (mm)] 5 wk after initiating therapy. Hearts exhibited higher cardiomyocyte nuclear [845 ± 22 VEGF 1 µg/kg vs. 519 ± 40 for saline (number/mm²)] and capillary [2,159 ± 119 VEGF 1 µg/kg vs. 1,590 ± 66 for saline (number/mm²)] densities. Myocardial analysis revealed 2.5 fold increase in Ki67+ cells and 2.8-fold increase in c-kit⁺ cells in the VEGF group, which provides evidence for cardiomyocyte regeneration and progenitor cell expansion. This study provides novel evidence of a salutary effect of VEGF in the cardiomyopathic hamster via induction of myogenic growth factor production by skeletal muscle and mobilization of progenitor cells, which resulted in attenuation of cardiomyopathy and repair of the heart.

vascular endothelial growth factor; -sarcoglycan; intramuscular injection