Increased susceptibility of HIF-1α heterozygous-null mice to cardiovascular malformations associated with maternal diabetes

Romana Bohuslavova, Lada Skvorova, David Sedmera, Gregg L. Semenza, Gabriela Pavlinkova

Research output: Contribution to journalArticlepeer-review

Abstract

Cardiovascular malformations are the most common manifestation of diabetic embryopathy. The molecular mechanisms underlying the teratogenic effect of maternal diabetes have not been fully elucidated. Using genome-wide expression profiling, we previously demonstrated that exposure to maternal diabetes resulted in dysregulation of the hypoxia-inducible factor 1 (HIF-1) pathway in the developing embryo. We thus considered a possible link between HIF-1-regulated pathways and the development of congenital malformations. HIF-1α heterozygous-null (Hif1a+/-) and wild type (Wt) littermate embryos were exposed to the intrauterine environment of a diabetic mother to analyze the frequency and morphology of congenital defects, and assess gene expression changes in Wt and Hif1a+/- embryos. We observed a decreased number of embryos per litter and an increased incidence of heart malformations, including atrioventricular septal defects and reduced myocardial mass, in diabetes-exposed Hif1a+/- embryos as compared to Wt embryos. We also detected significant differences in the expression of key cardiac transcription factors, including Nkx2.5, Tbx5, and Mef2C, in diabetes-exposed Hif1a+/- embryonic hearts compared to Wt littermates. Thus, partial global HIF-1α deficiency alters gene expression in the developing heart and increases susceptibility to congenital defects in a mouse model of diabetic pregnancy.

Original languageEnglish (US)
Pages (from-to)129-141
Number of pages13
JournalJournal of Molecular and Cellular Cardiology
Volume60
Issue number1
DOIs
StatePublished - Jul 2013

Keywords

  • Diabetic embryopathy
  • Heart defect
  • Hypoxia-inducible factor 1 alpha

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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