Role of HIF-1α in maternal hyperglycemia-induced embryonic vasculopathy

OBJECTIVE: Maternal diabetes adversely impacts embryonic vasculogenesis, which results in embryonic vasculopathy. The purpose of our study is to determine whether hypoxia inducible factor (HIF)-1 alpha plays a role in diabetic embryonic vasculopathy. STUDY DESIGN: Levels of HIF-1 alpha were determined in mouse conceptuses. Conceptuses on day 7 of pregnancy were cultured under euglycemic (150 mg/dL glucose) and hyperglycemic (300 mg/dL) conditions with or without AdCA5, or in the presence or absence of 2.0 mu g/mL human recombinant thioredoxin, an endogenous antioxidant protein. AdCA5 is an adenovirus encoding a constitutively active form of HIF-1 alpha. RESULTS: Maternal diabetes significantly reduced HIF-1 alpha protein expression. The administration of 1 mu L (1 x 10(7) infectious units/mL) per 1 mL culture medium AdCA5 completely reversed hyperglycemia-reduced vasculature morphological scores and vascular endothelial growth factor expression. Thioredoxin treatment reversed hyperglycemia-reduced HIF-1 alpha levels. CONCLUSION: We conclude that reduced HIF-1 alpha plays a critical role in the induction of diabetic embryonic vasculopathy, and that oxidative stress is implicated in hyperglycemia-induced HIF-1 alpha reduction.