Intramuscular VEGF repairs the failing heart: role of host-derived growth factors and mobilization of progenitor cells.
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-A(165) (0.1-1 microg/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 microg/kg vs. 364 +/- 19 for saline (number/mm(2)) saline] and capillary [591 +/- 80 VEGF 1 microg/kg vs. 342 +/- 21 for saline (number/mm(2))] densities. Skeletal muscle analysis revealed an increase in Ki67(+) nuclei in the VEGF 1 microg/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 microg/kg vs. 0.45 +/- 0.01 mm for saline) and an attenuation in ventricular dilation [5.59 +/- 0.12 VEGF 1 microg/kg vs. 6.03 +/- 0.09 for saline (mm)] 5 wk after initiating therapy. Hearts exhibited higher cardiomyocyte nuclear [845 +/- 22 VEGF 1 microg/kg vs. 519 +/- 40 for saline (number/mm(2))] and capillary [2,159 +/- 119 VEGF 1 microg/kg vs. 1,590 +/- 66 for saline (number/mm(2))] densities. Myocardial analysis revealed approximately 2.5 fold increase in Ki67+ cells and approximately 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.
Zisa
David
D
Department of Biochemistry and Center for Research in Cardiovascular Medicine, University at Buffalo, Buffalo, New York 14214, USA.
Shabbir
Arsalan
A
Mastri
Michalis
M
Suzuki
Gen
G
Lee
Techung
T
D042683:Angiopoietin-1 / Q000378:metabolism; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism; D006224:Cricetinae; D004195:Disease Models, Animal; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006321:Heart / Q000502:physiology; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D007273:Injections, Intramuscular; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D018482:Muscle, Skeletal / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D012038:Regeneration / Q000187:drug effects; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D013318:Stroke Volume / Q000187:drug effects / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
D042683:Angiopoietin-1; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D017228:Hepatocyte Growth Factor