Sex-specific Impact of Selective Reduced Uterine Placental Perfusion Model of Preeclampsia on Fetal Cardiac Maturation and Mitochondrial Function

Preeclampsia is a serious pregnancy complication and increases the risk of cardiovascular disease in offspring later in life. Cardiac development includes maturation of cardiomyocytes, a process that is intricately dependent on proper mitochondrial function. However, it remains unclear whether preeclampsia impairs mitochondrial function and alters cardiac maturation of fetal hearts during late gestation. Herein we induced selective reduced uterine placental perfusion (sRUPP), as a model of preeclampsia in rats, to investigate fetal cardiac myosin heavy chain (MYH) expression, reactive oxygen species (ROS) production, mitochondrial respiration, mitochondrial content and dynamics in male and female fetuses at gestational day (GD) 20 (term = GD 22). Litter size was reduced, while pup reabsorptions were increased in sRUPP compared to Sham controls. In only the male fetuses of sRUPP dams, cardiac MYH7/MYH6 ratio was reduced and MYH6 expression increased. Complex IV activity was elevated in sRUPP male fetuses, with no changes in mitochondrial citrate synthase or ATP synthase activities in either sex. However, ROS production increased in only sRUPP female fetuses. In male fetal hearts, sRUPP increased fusion protein MFN1 expression, tended to decrease fusion protein OPA1 expression, and decreased fission protein FIS1 expression. In contrast, MFN2 and OPA1 were reduced in sRUPP female fetuses. In conclusion, the sRUPP model of preeclampsia affected cardiac maturation and mitochondrial function in late gestation fetuses in a sex-specific manner. As prenatal strategies are being developed to improve pregnancy outcomes, sex-specific fetal effects should be taken into consideration.