NADPH oxidase 2-derived superoxide downregulates endothelial KCa3.1 in preeclampsia

Abstract Endothelial dysfunction is associated with K Ca 3.1 dysfunction and contributes to the development of hypertension in preeclampsia. However, evidence of endothelial K Ca 3.1 dysfunction in the vascular system from women with preeclampsia is still lacking. Therefore, we examined whether endothelial K Ca 3.1 dysfunction occurs in vessels from women with preeclampsia. We compared K Ca 3.1 and NADPH oxidase (NOX) expression in umbilical vessels and primary cultured human umbilical vein endothelial cells (HUVECs) from normal (NP; n =17) and preeclamptic pregnancy (PE; n =19) and examined the effects of plasma from NP or PE on K Ca 3.1 and NOX2 expression in primary cultured HUVECs from NP or human uterine microvascular endothelial cells. The endothelial K Ca 3.1 was downregulated, and NOX2 was upregulated, in umbilical vessels and HUVECs from PE, compared with those from NP. In addition, HUVECs from PE showed a significant decrease in K Ca 3.1 current. Plasma from PE induced K Ca 3.1 down regulation, NOX2 upregulation, phosphorylated-p38 mitogen-activated protein kinase downregulation, and superoxide generation, and these effects were prevented by antioxidants (tempol or tiron), NOX2 inhibition, or anti-lectin-like oxidized low-density lipoprotein (LDL) receptor 1 (LOX1) antibody. Oxidized LDL and the superoxide donor xanthine/xanthine oxidase mixture induced K Ca 3.1 downregulation. In contrast, plasma from PE did not generate hydrogen peroxide, and the hydrogen peroxide donor tert -butylhydroperoxide induced K Ca 3.1 upregulation. These results provide the first evidence that plasma from PE generates superoxide via a LOX1–NOX2-mediated pathway and downregulates endothelial K Ca 3.1, which may contribute to endothelial dysfunction and vasculopathy in preeclampsia. This suggests K Ca 3.1as a novel target for patients with preeclampsia.