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45: Role of HIF-1alpha in maternal hyperglycemia-induced embryonic vasculopathy

      Objective

      Maternal diabetes adversely impacts embryonic vasculogenesis resulting in embryonic vasculopathy. This, in turn, leads to malformations and/or embryonic lethality. HIF-1α, an oxygen sensitive subunit of HIF-1, is essential for normal embryonic vasculogenesis. The purpose of our study is to determine whether HIF-1α plays a role in diabetic embryonic vasculopathy.

      Study Design

      Protein and mRNA levels of HIF-1〈 were determined in embryonic day 7 (E7) and E8 conceptuses from non-diabetic and diabetic mice. E7 conceptuses were cultured for 24h or 48h under euglycemic (150 mg/dl glucose) and hyperglycemic (300 mg/dl) conditions in the presence or absence of 0.5 ⌈l or 1 ⌈l (1x107 IFU/ml) AdCA5 per 1ml culture medium, or in the presence or absence of 2.0 ⌈g/ml human recombinant thioredoxin (Trx), an endogenous anti-oxidant protein. AdCA5 is an adenovirus encoding a constitutively active form of HIF-1〈.

      Results

      Maternal diabetes significantly reduced HIF-1〈 protein in both E7 and E8 conceptuses. In contrast, maternal diabetes did not alter HIF-1〈 mRNA levels, suggesting that diabetes regulates HIF-1〈protein stability. The administration of 0.5 ⌈l AdCA5 increased hyperglycemia-reduced vasculature morphological scores. In addition, 1 ⌈l AdCA5 completely reversed hyperglycemia-reduced vasculature morphological scores, and AdCA5 reversed hyperglycemia-reduced VEGF protein expression. Trx treatment reversed hyperglycemia-reduced HIF-1〈 levels.

      Conclusions

      We conclude that reduced HIF-1〈 plays a critical role in the induction of diabetic embryonic vasculopathy and hyperglycemia-induced VEGF reduction. Because Trx blocks hyperglycemia-reduced HIF-1〈, oxidative stress is implicated in the reduction of HIF-1〈 by hyperglycemia.