Major congenital malformations, including those affecting the cardiovascular system, remain the leading cause of mortality and morbidity in infants of diabetic mothers. Interestingly, targeted mutations of several genes (including VEGF and VEGF receptors) and many teratogenic agents (including excess D-glucose) that give rise to embryonic lethal phenotypes during organogenesis are associated with a failure in the formation and/or maintenance of a functional vitelline circulation. Given the similarities in the pathology of the abnormal vitelline circulation in many of these conditions, we hypothesized that the hyperglycemic insult present in diabetes could cause the resultant abnormalities in the vitelline circulation by affecting VEGF/VEGF receptor signaling pathway(s). In this study we report that hyperglycemic insult results in reduced levels of VEGF-A in the conceptus, which in turn, leads to abnormal VEGF receptor signaling, ultimately resulting in embryonic (vitelline) vasculopathy. These findings and our observation that addition of exogenous rVEGF-A(165) within a defined concentration range blunts the hyperglycemia-induced vasculopathy in the conceptus support the concept that VEGF levels can be modulated by glucose levels. In addition, these findings may ultimately lead to novel therapeutic approaches for the treatment of selected congenital cardiovascular abnormalities associated with diabetes.