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

Abstract

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.

Rodent models of heart failure: an updated review

“…With regard to cardiomyocyte loss, numerous studies showed autophagic vacuolar degeneration in cardiomyocytes, which could be improved by treatment with granulocyte colony-stimulating factor [288]. Another report provided novel evidence of a beneficial effect of vascular endothelial growth factor in the Syrian CM 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 [328].…”

Autologous Mesenchymal Stem Cells Mobilize cKit + and CD133 + Bone Marrow Progenitor Cells and Improve Regional Function in Hibernating Myocardium

“…23 Likewise, studies with skeletal muscle injection of porcine MSCs into Syrian hamsters 24 and MSCs that overexpressed insulin-like growth factor-1 9 and Akt 20 in infarcted animals support the notion that paracrine factors can mobilize BMPCs and potentially facilitate cardiac repair. On the basis of these observations, the known secretion of a variety of growth factors from MSCs, 24,25 and the demonstrated ability of selected growth factors to mobilize BMPCs, 26 we tested the hypothesis that MSCs stimulate myocyte proliferation through a similar mechanism. To more definitively ascertain the effects of MSCs on angiogenesis and myocyte regeneration independent of infarct volume, we used an in vivo model of hibernating myocardium.…”

“…25 In our previous studies in the Syrian hamster with heart failure, we demonstrated the potential role of paracrine factors in mobilizing BMPCs after repetitive skeletal muscle injection of porcine MSCs, MSC media, and vascular endothelial growth factor. 24,26,52,53 The effects of single injections of MSC media in swine are controversial. 38,54 Some of the paracrine candidates secreted by porcine MSCs include vascular endothelial growth factor, insulin-like growth factor-1, and interleukin-6, and we Given the ability of CD133 ϩ BMPCs to coexpress cardiac lineage markers, including GATA-4, Nkx2.5, and troponin I, we propose that some of the myocyte proliferation that results from icMSCs reflects the transdifferentiation of endogenous BMPCs mobilized to the heart.…”

“…On the basis of these observations, the known secretion of a variety of growth factors from MSCs, 24,25 and the demonstrated ability of selected growth factors to mobilize BMPCs, 26 we tested the hypothesis that MSCs stimulate myocyte proliferation through a similar mechanism. To more definitively ascertain the effects of MSCs on angiogenesis and myocyte regeneration independent of infarct volume, we used an in vivo model of hibernating myocardium.…”

Enhancing the efficacy of mesenchymal stem cell therapy

“…The strategies outlined in this review offer a testable platform to launch innovative clinical trials based on rational design of MSC therapy. [6,30,31,45,126] .…”