Placental small extracellular vesicles and cardiac mitochondrial dynamics in preeclampsia

Abstract Preeclampsia is a hypertensive disorder of pregnancy that confers a markedly increased risk of maternal cardiovascular disease, yet the mechanisms linking placental pathology to maternal cardiac dysfunction remain poorly understood. Placental hypoxia is a central feature of early-onset preeclampsia (E-PE) and promotes the systemic release of placental debris, including bioactive extracellular vesicles, emerging mediators of placenta-to-maternal communication capable of modulating maternal physiology. Using a placenta-specific Phd2 conditional knockout mouse model that recapitulates human E-PE, we identified maternal cardiac structural and functional abnormalities accompanied by pronounced mitochondrial ultrastructural disruption and enhanced mitochondrial fission in the left ventricular myocardium. Hence, we next investigated whether placenta-derived small extracellular vesicles (P-sEVs) contribute to maternal cardiac mitochondrial remodeling in preeclampsia. Circulating P-sEVs isolated from both murine and human preeclamptic pregnancies induced DRP1-dependent mitochondrial fragmentation and increased endoplasmic reticulum-mitochondria tethering in human cardiomyocytes in vitro. Exposure to preeclamptic P-sEVs reduced cellular ATP levels and impaired mitochondrial membrane potential without affecting cardiomyocyte viability, consistent with impaired mitochondrial bioenergetics. Lipidomic profiling by LC-MS/MS revealed enrichment of bioactive ceramide and sphingomyelin species in preeclamptic P-sEVs, which were sufficient to recapitulate mitochondrial remodeling in cardiomyocytes. Disrupting sphingolipid metabolism in hypoxia-exposed H9-cytotrophoblasts attenuated the capacity of their sEVs to induce DRP1-mitochondrial colocalization in recipient human cardiomyocytes. Importantly, pharmacological inhibition of placental HIF-1 signaling attenuated the ability of preeclamptic P-sEVs to disrupt cardiomyocyte mitochondrial dynamics. Together, these findings identify maternal circulating placental sEVs as previously unrecognized contributors to cardiomyocyte mitochondrial homeostasis and define a placenta-heart signaling axis through which placental hypoxic stress drives maternal cardiac mitochondrial remodeling in preeclampsia.