Severe early-onset preeclampsia is significantly associated with metabolic dysregulation and sustained elevation of placental HIF-1α

INTRODUCTION: Hypoxia-inducible factor 1α is an oxygen-sensitive transcription factor which has been reported to be upregulated in placentas of preeclampsia patients beyond the first trimester. In this study, we sought to determine how HIF-1α protein remains elevated in severe, early-onset PE and impacts placental metabolic function. METHODS: Placentas from healthy pregnant control and severe, early-onset preeclampsia patients were taken at the time of delivery and processed for Western blot analysis, glutathione levels, and mitochondrial copy number. RESULTS: HIF-1α protein was significantly elevated in sEOPE. VHL, which degrades HIF-1α, was significantly decreased; while AKT, which stabilizes HIF-1α protein, was significantly elevated. A decrease in VHL, coupled with increased AKT, contribute to the sustained elevation of placental HIF-1α. We then assessed downstream metabolic targets to determine the impact of elevated HIF-1α. Target proteins in glycolysis were significantly elevated. An enzyme critical for β-oxidation was significantly decreased. The master regulator of cellular energy sensing, pAMPK, was significantly elevated, suggesting low cellular energy. Low cellular energy has been shown to decrease antioxidant capacity, consistent with our finding of decreased glutathione and GPX4. HTRA4, an indicator of endothelial dysfunction was also significantly elevated, further supporting increased placental metabolic dysfunction. CONCLUSION: Severe, early-onset preeclampsia is known to occur due to abnormal placentation, leading to compromised placental oxygen signaling and a sustained elevation of HIF-1α. This results in a shift from oxidative phosphorylation to glycolysis, decreased cellular energy, and diminished antioxidant capacity. Our findings provide compelling evidence for the significance of elevated placental HIF-1α in the pathogenesis of sEOPE.