Intramuscular vascular endothelial growth factor therapy for heart failure: Roles of host derived factors and mobilization of bone marrow progenitor cells
Zisa, David Christopher
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Heart failure is a significant cause of morbidity and mortality worldwide. Currently, the only curative therapy for heart failure is heart transplantation and therefore alternative therapies are needed. Vascular endothelial growth factor (VEGF), a potent angiogenic factor, has primarily been explored for the treatment of cardiovascular and peripheral vascular ischemia. Recent evidence has emerged that VEGF may also have direct regenerative effects on injured muscle. Given the reported findings that VEGF may promote muscle regeneration directly, along with the finding that Mesenchymal Stem Cells (MSCs) secrete an abundance of VEGF, we investigated whether cell free VEGF therapy could activate skeletal muscle and promote heart repair in the cardiomyopathic delta-sarcoglycan null hamster. VEGF had significant migratory, proliferative, and mitogenic effects on skeletal myocytes. In addition, VEGF was delivered intramuscularly into the skeletal muscle of the delta-sarcoglycan null hamster. This non-invasive approach resulted in significant local skeletal muscle regeneration and amplification of growth factors. Furthermore, we found that VEGF therapy improved ventricular function, which was accompanied by significant regenerative effects including increased capillary and nuclear density, expansion of c-kit + progenitor cells, and increased cell proliferation. VEGF therapy also resulted in elevation of plasma stromal cell derived factor 1 (SDF1) levels and significant progenitor cell mobilization. VEGF administration resulted in increased phosphorylation of AKT in both skeletal and cardiac muscle, as well as increased phosphorylation of ERK1/2 in the heart. Phosphorylation and activation of the AKT and ERK pathways play a crucial role in VEGF induced heart repair and regeneration in cardiomyopathy. We investigated whether beneficial effects of intramuscular VEGF therapy on heart failure may be occurring through induction of SDF1 and its regulation of progenitor cell mobilization to the heart. The concomitant use of an SDF1 blocking antibody along with VEGF therapy resulted in a reduction in the improvement of cardiac function, progenitor cell mobilization, and cardiac regeneration as well as an increase in myocardial injury. A cardiac and skeletal muscle repair mechanism mediated by both amplification of trophic factors and mobilization of progenitor cells in response to VEGF therapy was identified.