Dysregulated Mitochondrial Calcium Causes Spiral Artery Remodeling Failure in Preeclampsia

作者：Xiyuan Lu, Yifan Wang, Yifan Wang, Na Geng, Zhiguo Zou, Xueqing Feng, Yuehong Wang, Yuehong Wang, Zhice Xu, Ning Zhang, Jun Pu · 发表于：Hypertension · 年份：2024 · DOI：10.1161/hypertensionaha.124.23046 · 被引用次数：11 · 研究领域：Pregnancy and preeclampsia studies、Birth, Development, and Health

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 ch...