A novel role for VEGF in endocardial cushion formation and its potential contribution to congenital heart defects

Normal cardiovascular development is exquisitely dependent on the correct d osage of the angiogenic growth factor and vascular morphogen vascular endot helial growth factor (VEGF). However, cardiac expression of VEGF is also ro bustly augmented during hypoxic insults, potentially mediating the well-est ablished teratogenic effects of hypoxia on heart development. We report tha t during normal heart morphogenesis VEGF is specifically upregulated in the atrioventricular (AV) field of the heart tube soon after the onset of endo cardial cushion formation (i.e. the endocardium-derived structures that bui ld the heart septa and valves). To model hypoxia-dependent induction of VEG F in vivo, we conditionally induced VEGF expression in the myocardium using a tetracycline-regulated transgenic system. Premature induction of myocard ial VEGF in E9.5 embryos to levels comparable with those induced by hypoxia prevented formation of endocardial cushions. When added to explanted embry onic AV tissue, VEGF fully inhibited endocardial-to-mesenchymal transformat ion. Transformation was also abrogated in AV explants subjected to experime ntal hypoxia but fully restored in the presence of an inhibitory soluble VE GF receptor 1 chimeric protein. Together, these results suggest a novel dev elopmental role for VEGF as a negative regulator of endocardial-to-mesenchy mal transformation that underlies the formation of endocardial cushions. Mo reover, ischemia-induced VEGF may be the molecular link between hypoxia and congenital defects in heart septation.