Congenital malformations occur in up to 10% of babies born to diabetic women. While hyperglycemia of maternal diabetes targets multiple organs, embryonic vasculature is the first system to be developed and is most vulnerable. Diabetes induces embryonic vasculopathy leading to embryonic lethality or neural tube defects (NTD). Maternal diabetes induces the reduction and apoptosis in vascular Flk1+ progenitors and reduces blood island numbers resulting in aberrant vasculogenesis. Our preliminary data suggest that correcting altered vascular signaling and vasculopathy leads to reduced NTD formation. We hypothesize that maternal diabetes-induced DNA hypermethylation causes the downregulation of FGF2 and BMP4, which enhances VEGFR1 expression leading to impaired VEGFR2 signaling, and that these events concomitantly result in vascular Flk1+ progenitor loss and vasculopathy. Reducing vasculopathy by restoring either FGF2 or BMP4 expression relieves cellular stress and blocks JNK1/2 and apoptosis in neuroepithelial cells leading to decreased NTD formation. Restoring both FGF2 and BMP4 expression prevents vasculopathy and NTD.
Aim 1 will determine the role of DNA hypermethylation in vascular gene silencing that leads to vasculopathy and NTD formation. Our working hypothesis is that DNA hypermethylation contributes to vascular gene silencing, and that the major causal factor in diabetic embryopathy, oxidative stress is responsible for DNA hypermethylation and vascular gene silencing.
Aim 2 will determine whether FGF2 reduction-induced vasculopathy causes NTD formation. We hypothesize that diabetes-suppressed FGF2 expression causes Flk1+ progenitor loss and impaired VEGFR2 signaling leading to vasculopathy and consequent NTD formation.
Aim 3 will determine whether restoring BMP4 expression in vasculature ameliorates vasculopathy and NTD formation. Our hypothesis is that BMP4 reduction mediates the pathogenic effect of maternal diabetes on vasculogenesis leading to NTD formation. Our application investigates novel maternal diabetes-altered vascular signaling at early development stages, proves a new concept that altered vascular signaling and resultant vasculopathy cause NTD, and overcomes existing barriers by proposing vascular Flk1+ progenitor viability and blood island formation as central steps in this disease process.
Nearly 3 million American women and 60 million women worldwide of reproductive age (18-44 years) have diabetes. 27% of them are not aware that they have diabetes. Diabetes-induced birth defects are significantly maternal-fetal health problems. The proposed study is to investigate the case of embryonic vasculopathy in diabetic pregnancies, and provide mechanistic evidence of DNA hypermethylation, FGF2, and BMP4 as targets for therapeutic interventions in this disease.
