Hyperglycemia-induced vasculopathy in the murine conceptus is mediated viareductions of VEGF-A expression and VEGF receptor activation

Major congenital malformations, Including those affecting the cardiovascula r system, remain the leading cause of mortality and morbidity In infants of diabetic mothers. Interestingly, targeted mutations of several genes (incl uding VEGF and VEGF receptors) and many teratogenic agents (including exces s D-glucose) that give rise to embryonic lethal phenotypes during organogen esis 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 hypot hesized that the hyperglycemic insult present hn diabetes could cause the r esultant abnormalitles in the vitelline circulation by affecting VEGF/VEGF receptor signaling pathway(s). In this study we report that hyperglycemic i nsult results in reduced levels of VEGF-A in the conceptus, which in turn, leads to abnormal VEGF receptor signaling, ultimately resulting in embryoni c (vitelline) vasculopathy. These findings and our observation that additio n of exogenous rVEGF-A(165) within a defined concentration range blunts the hyperglycemia-induced vasculopathy in the conceptus support the concept th at VEGF levels can be modulated by glucose levels. In addition, these findi ngs may ultimately lead to novel therapeutic approaches for the treatment o f selected congenital cardiovascular abnormalities associated with diabetes .