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Vascular endothelial growth factor promotes cardiomyocyte differentiation of embryonic stem cells

¹Cardiovascular Division, Department of Medicine, the Charles A. Dana Research Institute and Harvard-Thorndike Laboratories, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; ²Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York; and ³Division of Cardiovascular Medicine, Caritas St. Elizabeth's Medical Center, Boston, Massachusetts

Submitted 12 April 2005 ; accepted in final form 3 May 2006

Embryonic stem cells (ESCs) overexpressing the vascular endothelial growth factor (VEGF) improve cardiac function in mouse models of myocardial ischemia and infarction by mechanisms that are poorly understood. Here we studied the effects of VEGF on cardiomyocyte differentiation of mouse ESCs in vitro. We used flow cytometry to determine the expression of -myosin heavy chain (-MHC), cardiac troponin I (cTn-I), and Nkx2.5 in differentiated ESCs. VEGF (20 ng/ml) significantly enhanced -MHC, cTn-I, and Nkx2.5 expression in differentiated ESCs. Western blot analysis confirmed these findings. We found that VEGF receptor FMS-like tyrosine kinase-1 (Flt-1) and fetal liver kinase-1 (Flk-1) expression increased during ESC differentiation. Antibodies against Flk-1 totally blocked and against Flt-1 partially blocked VEGF-induced NKx2.5-positive-stained cells. The ERK inhibitor PD-098059 abolished VEGF-induced cardiomyocyte differentiation of ESCs. Our results suggest that VEGF promotes cardiomyocyte differentiation predominantly by ERK-mediated Flk-1 activation and, to a lesser extent, by Flt-1 activation. These findings may be of significance for stem cell and growth factor therapies to regenerate failing cardiomyocytes.

cardiac-specific proteins; Flt-1 and Flk-1; extracellular signal-regulated kinase

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