Impaired Mitochondrial Calcium Homeostasis Induces Failed Remodeling of the Spiral Artery in Preeclampsia

Abstract

ABSTRACTRATIONALEPreeclampsia (PE) is a hypertensive disorder that occurs during pregnancy and is characterized by failed spiral artery remodeling. Calcium deficiency in women has been strongly linked to an increased risk of developing PE. Mitochondrial calcium ([Ca2+]m) homeostasis is essential to regulate vascular smooth muscle cell (VSMC) function. However, the role of [Ca2+]min PE development remains largely unknown.METHODSTo investigate this, we measured vessel tone on isolated human spiral arteries obtained from normotensive and hypertensive pregnant women. The PE rat model was induced with L-NAME treatment.RESULTSOur initial findings revealed compromised vessel function in spiral arteries derived from PE patients, as evidenced by diminished vasoconstriction and vasodilation responses to angiotensin II and sodium nitroprusside, respectively. Moreover, the spiral artery VSMCs from PE patients exhibited phenotypic transformation and proliferation associated with imbalanced [Ca2+]mhomeostasis. Subsequent in vitro experiments employing gain- and loss-of-function approaches demonstrated that mitochondrial Na+/Ca2+exchanger (mtNCLX) played a role in promoting VSMCs phenotypic switching and impaired mitochondrial functions. Furthermore, the utilization of the pharmacological inhibitor CGP37157 to block mtNCLX revealed a significant attenuation of VSMC phenotypic switching and restoration of normal mitochondrial function in both the spiral arteries of PE patients and a PE rat model.CONCLUSIONSThis study provides comprehensive evidence supporting the significance of [Ca2+]min VSMCs of spiral arteries, shedding light on its association with VSMC phenotypic switching and the compromised remodeling of spiral arteries in PE. The findings suggest that targeting the mtNCLX holds promise as a novel therapeutic approach for the management of PE.GRAPHIC ABSTRACTGraphic abstract is available for this article.