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 20 (GD 20) (term = GD 22). Litter size was reduced, whereas pup reabsorptions were increased in sRUPP compared with 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.NEW & NOTEWORTHY This study assessed the impact of preeclampsia on late gestation fetal cardiac development using a rat model of reduced uterine placental perfusion. Our findings revealed sex-specific differences: male fetuses exhibited accelerated cardiac maturation and complex IV activity, whereas female fetuses showed evidence of oxidative stress in the cardiac tissue. Disruptions in mitochondrial dynamics were observed in both sexes. These results underscore the necessity of considering sex-specific fetal effects when developing prenatal therapeutic interventions for preeclampsia.