Maternal Cardiovascular Adaptations in Rodent Models of Pregnancy Complications

Abstract

Pregnancy induces a myriad of time-dependent changes to the maternal cardiovascular (CV) system and correct orchestration of these adaptations is vital for pregnancy success and future health of both mother and offspring. Complications in human pregnancy such as preeclampsia (PE) and gestational diabetes are associated with aberrant gestation-induced adaptations of the maternal CV system and adverse pregnancy outcomes. This thesis explores how several pre-existing conditions affect pregnancy. It is hypothesized that the response of the rodent maternal CV system to the burden of pregnancy will be impaired when challenged with preexisting metabolic distress, impaired angiogenesis or underlying, subclinical congenital heart defects, and these stressors will compromise fetal health. To study the effects of metabolic distress on pregnancy, the non-obese diabetic (NOD) mouse was used as a model of human diabetes. Diabetic mice exhibited a blunted maternal cardiac response to pregnancy with concomitant renal pathologies. Offspring were afflicted with CV abnormalities and decreased body weight. The link between PE and reduced maternal serum levels of placental growth factor (PGF) prompted the study of Pgf-/- mice. Knockout mice exhibited altered gestation-induced hemodynamic and CV responses, suggestive of a cardioprotective role of PGF during pregnancy. This altered maternal phenotype did not affect fetal blood flow but resulted in decreased fetal weights. Although congenital heart defects are the most common birth anomaly, their impact on postnatal adaptation to pregnancy is unknown. To investigate this, dimethadione (DMO), the N-demethylated metabolite of the anticonvulsant trimethadione, was administered to pregnant rats to produce offspring with ventricular septal defects. These deficits resolved as animals matured, reflecting a similar clinical phenomenon. Despite absence of persistent structural or functional abnormalities, treated rats exhibited altered CV and hemodynamic responses to pregnancy, suggesting latent CV dysfunction. Offspring of these previously treated dams presented with increased body and placental weight. ii Together, work performed in this thesis emphasizes the importance of maternal CV adaptions not only for pregnancy success but health of the offspring. Results also underscore the role of PGF in gestational CV adaptations and the impact of in utero chemical exposures on the postnatal capacity to adapt to pregnancy.