Dysregulated Mitochondrial Calcium Causes Spiral Artery Remodeling Failure in Preeclampsia

BACKGROUND: Calcium deficiency in women is strongly linked to an increased risk of developing preeclampsia. Mitochondrial calcium ([Ca 2+ ] m ) homeostasis is essential to regulate vascular smooth muscle cell (VSMC) function. However, the role of [Ca 2+ ] m in preeclampsia development remains largely unknown. METHODS: To investigate this, human spiral arteries obtained from normotensive and preeclamptic women were collected for vascular function, RNA sequencing, and VSMC studies. N(ω)-nitro-L-arginine methyl ester–induced preeclampsia animal experiments were established to investigate the effects of intervening in [Ca 2+ ] m to improve the outcome for preeclamptic mothers or their infants. RESULTS: Our initial findings revealed compromised vessel function in spiral arteries derived from patients with preeclampsia, as evidenced by diminished vasoconstriction and vasodilation responses to angiotensin II and sodium nitroprusside, respectively. Moreover, the spiral artery VSMCs from patients with preeclampsia exhibited phenotypic transformation and proliferation associated with the disrupted regulatory mechanisms of [Ca 2+ ] m uptake. Subsequent in vitro experiments employing gain- and loss-of-function approaches demonstrated that the mitochondrial Na + /Ca 2+ exchanger played a role in promoting phenotypic switching and impaired mitochondrial functions in VSMCs. Furthermore, mtNCLX (mitochondrial Na + /Ca 2+ exchanger) inhibitor CGP37157 significantly improved VSMC phenotypic changes and restored mitochondrial function in both patients with preeclampsia–derived VSMCs and the preeclampsia rat model. CONCLUSIONS: This study provides comprehensive evidence supporting the disrupted regulatory mechanisms of [Ca 2+ ] m uptake in VSMCs of spiral arteries of patients with preeclampsia and further elucidates its correlation with VSMC phenotypic switching and defective spiral artery remodeling. The findings suggest that targeting mtNCLX holds promise as a novel therapeutic approach for managing preeclampsia.