BACKGROUND Calcium deficiency in women is strongly linked to an increased risk of developing preeclampsia. Mitochondrial calcium ([Ca2+]m) homeostasis is essential to regulate vascular smooth muscle cell (VSMC) function. However, the role of [Ca2+]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 [Ca2+]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 [Ca2+]m uptake. Subsequent in vitro experiments employing gain- and loss-of-function approaches demonstrated that the mitochondrial Na+/Ca2+ exchanger played a role in promoting phenotypic switching and impaired mitochondrial functions in VSMCs. Furthermore, mtNCLX (mitochondrial Na+/Ca2+ 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 [Ca2+]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.

中文翻译：

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线粒体钙失调导致子痫前期螺旋动脉重塑失败。


背景 女性缺钙与患子痫前期的风险增加密切相关。线粒体钙 （[Ca2+]m） 稳态对于调节血管平滑肌细胞 （VSMC） 功能至关重要。然而，[Ca2+]m 在子痫前期发展中的作用在很大程度上仍然未知。方法 为了研究这一点，收集了从血压正常和子痫前期女性获得的人螺旋动脉用于血管功能、RNA 测序和 VSMC 研究。建立了 N（ω）-硝基-L-精氨酸甲酯诱导的子痫前期动物实验，以研究干预 [Ca2+]m 对改善子痫前期母亲或其婴儿预后的影响。结果我们的初步发现揭示了子痫前期患者螺旋动脉的血管功能受损，分别表现为对血管紧张素 II 和硝普钠的血管收缩和血管舒张反应减弱。此外，子痫前期患者的螺旋动脉 VSMC 表现出与 [Ca2+]m 摄取调节机制中断相关的表型转化和增殖。随后采用功能增益和丧失方法的体外实验表明，线粒体 Na + / Ca2 + 交换器在促进 VSMC 的表型转换和线粒体功能受损中发挥作用。此外，mtNCLX （线粒体 Na+/Ca2+ 交换剂） 抑制剂CGP37157显著改善子痫前期来源的 VSMC 患者和子痫前期大鼠模型的 VSMC 表型变化并恢复线粒体功能。 结论 本研究提供了全面的证据，支持子痫前期患者螺旋动脉 VSMCs 中 [Ca2+]m 摄取的调节机制被破坏，并进一步阐明其与 VSMC 表型转换和螺旋动脉重塑缺陷的相关性。研究结果表明，靶向 mtNCLX 有望成为治疗子痫前期的新型治疗方法。