肿瘤坏死因子-α抑制子宫动脉内皮细胞的妊娠适应钙信号。

TNF-alpha inhibits pregnancy-adapted Ca signaling in uterine artery endothelial cells.

机构信息

Perinatal Research Laboratories, Department of Obstetrics and Gynecology, School Medicine and Public Health, University of Wisconsin-Madison, 7E Unity Point Health-Meriter Hospital, 202 South Park Street, Madison, WI, 53715, USA.

出版信息

Mol Cell Endocrinol. 2019 May 15;488:14-24. doi: 10.1016/j.mce.2019.02.008. Epub 2019 Feb 16.

Enhancement of vasodilation of uterine arteries during pregnancy occurs through increased connexin (Cx)43 gap junction (GJ) communication supporting more frequent and sustained Ca 'bursts'. Such adaptation is lacking in subjects with preeclampsia (PE). Here we show TNF-alpha, commonly increased in PE subjects, inhibits Cx43 function and Ca bursts in pregnancy-derived ovine uterine artery endothelial cells (P-UAEC) via Src and MEK/ERK phosphorylation of Cx43, and this can be reversed by PP2 or U0126. Of relevance to humans: (1) the nutraceutical Src antagonist t10, c12 CLA also recovers Ca bursting in P-UAEC. (2) TNF-alpha can reduce and PP2 rescue Ca bursting and NO output in human umbilical vein endothelium (HUV Endo) preparations. (3) Treatment of HUV Endo from PE subjects with PP2 alone can rescue bursting and NO output. We conclude TNF-alpha acts via Src more than MEK/ERK to inhibit GJ Cx43 function in PE subjects, and CLA may offer a potential therapy.

妊娠期间子宫动脉的血管舒张增强是通过增加缝隙连接（Cx）43 间隙连接（GJ）通讯来实现的，这支持更频繁和更持续的 Ca'爆发'。这种适应性在患有先兆子痫（PE）的患者中缺乏。在这里，我们表明，通常在 PE 患者中增加的 TNF-α通过 Cx43 的Src 和 MEK/ERK 磷酸化来抑制妊娠衍生的绵羊子宫动脉内皮细胞（P-UAEC）中的 Cx43 功能和 Ca 爆发，这可以通过 PP2 或 U0126 逆转。与人类相关的是：（1）营养 Src 拮抗剂 t10，c12 CLA 也可以恢复 P-UAEC 中的 Ca 爆发。（2）TNF-α可以减少和 PP2 恢复 Ca 爆发和人脐静脉内皮细胞（HUV Endo）制剂中的 NO 输出。（3）单独用 PP2 处理 PE 患者的 HUV Endo 可以挽救爆发和 NO 输出。我们得出结论，TNF-α通过Src 而不是 MEK/ERK 起作用，以抑制 PE 患者中的 GJ Cx43 功能，CLA 可能提供一种潜在的治疗方法。