TY - JOUR
T1 - Increased susceptibility of HIF-1α heterozygous-null mice to cardiovascular malformations associated with maternal diabetes
AU - Bohuslavova, Romana
AU - Skvorova, Lada
AU - Sedmera, David
AU - Semenza, Gregg L.
AU - Pavlinkova, Gabriela
N1 - Funding Information:
This work was funded by a Marie Curie International Reintegration Grant within the 7th European Community Framework Programme PIRG02-GA-2007-224760; grants from the Czech Ministry of Education, Youth and Sports AVOZ50520701; and the Czech Science Foundation 301/09/0117 and 302/11/1308.
PY - 2013/7
Y1 - 2013/7
N2 - 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.
AB - 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.
KW - Diabetic embryopathy
KW - Heart defect
KW - Hypoxia-inducible factor 1 alpha
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U2 - 10.1016/j.yjmcc.2013.04.015
DO - 10.1016/j.yjmcc.2013.04.015
M3 - Article
C2 - 23619295
AN - SCOPUS:84877675746
SN - 0022-2828
VL - 60
SP - 129
EP - 141
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
IS - 1
ER -