Placental and fetal characteristics of the Ohia mouse line recapitulate outcomes in human hypoplastic left heart syndrome

Congenital heart defects (CHDs) are one of the most common birth defects worldwide. The morbidity and mortality associated with these defects is compounded by increased frequency of fetal growth abnormalities in the newborns. Inappropriate placental development and function has been implicated as a contributing factor to poor fetal growth in pregnancies complicated by CHDs however, the exact mechanisms are poorly understood. In the Ohia mouse model of hypoplastic left heart syndrome (HLHS), the double homozygous genotype had previously been shown to be embryonically lethal at mid-pregnancy; a time in which optimal establishment of the placenta is crucial to fetal survival. We aimed to characterize placental and fetal growth and development in the double heterozygous genotype to determine whether the genetic mutations associated with HLHS in the Ohia mouse also affect the placenta. The frequency of fetuses with reduced weight near term was shifted in the double heterozygous genotype compared to wildtype fetuses. This shift in fetal weight distribution was associated with reduced fetal capillary density in the placentas of the double heterozygotes as well as a reduction in placental mRNA expression of angiogenic factors placenta growth factor (Pgf) and fms-like tyrosine kinase-1 (Flt1) suggesting abhorrent placental angiogenesis. Positive correlations were observed between fetal weight and placenta mRNA expression of several nutrient transporters in the double heterozygous genotype but not observed in the wildtype. This data shows changes to placental angiogenesis and nutrient transport that are likely to contribute to inadequate fetal growth in the Ohia mouse model. Such differences are similar to findings in studies of human placentas from pregnancies with a fetus with HLHS and highlights the importance of this mouse model in continuing to understand the link between placental development and CHDs such as HLHS.