TNF-alpha inhibits pregnancy-adapted Ca2+ signaling in uterine artery endothelial cells

Enhancement of vasodilation of uterine arteries during pregnancy occurs through increased connexin (Cx)43 gap junction (GJ) communication supporting more frequent and sustained Ca2+ ‘bursts’. Such adaptation is lacking in subjects with preeclampsia (PE). Here we show TNF-alpha, commonly increased in PE subjects, inhibits Cx43 function and Ca2+ 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 Ca2+ bursting in P-UAEC. (2) TNF-alpha can reduce and PP2 rescue Ca2+ 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. •Pregnancy is associated with enhanced Ca2+ signaling in UA endothelial cells, mediated by enhanced Cx43 connectivity.•We now show TNF-alpha inhibits Cx43 function and so periodic Ca2+ bursts in pregnancy-derived UA endothelial cells.•TNF acts via Src to inhibit Cx43 by causing phosphorylation directly at positions 265 and indirectly at position 279/282.•TNF action is reversed by the Src inhibitor PP2 or the nutraceutical Src antagonist t10,c12 CLA or MEK/ERK inhibitor U0126.•In umbilical vessels from preeclamptic subjects, Src inhibitors promotes rescue of otherwise impaired Ca2+ and NO responses.