title: Increased susceptibility of HIF-1α heterozygous-null mice to cardiovascular malformations associated with maternal diabetes.
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.
authors.affiliation: Institute of Biotechnology AS CR, Prague, Czech Republic.
authors.forename: Romana
authors.initials: R
authors.lastname: Bohuslavova
authors.forename: Lada
authors.initials: L
authors.lastname: Skvorova
authors.forename: David
authors.initials: D
authors.lastname: Sedmera
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
authors.forename: Gabriela
authors.initials: G
authors.lastname: Pavlinkova
mesh_terms: D000818:Animals; D004622:Embryo, Mammalian / Q000196:embryology* / Q000473:pathology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006321:Heart / Q000196:embryology*; D006330:Heart Defects, Congenital / Q000196:embryology* / Q000235:genetics / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051379:Mice; D008817:Mice, Mutant Strains; D009124:Muscle Proteins / Q000096:biosynthesis* / Q000235:genetics; D011247:Pregnancy; D011254:Pregnancy in Diabetics / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009124:Muscle Proteins