Altered redox state modulates endothelial K _Ca 2.3 and K _Ca 3.1 levels in normal pregnancy and preeclampsia

Aims: Altered redox state has been related to the development of normal pregnancy (NP) and preeclampsia (PE). Endothelial K _Ca 2.3 and K _Ca 3.1 (K _Ca s) play an important role in vasodilation, and K _Ca s levels are affected by oxidative stress. We investigated the mechanisms of oxidative stress-mediated K _Ca s expression modulation during NP and PE. Results: Human uterine microvascular endothelial cells were incubated in serum from normal nonpregnant women (n = 13) and women with NP (n = 24) or PE (n = 15), or in vascular endothelial growth factor (VEGF), oxidized low-density lipoprotein (ox-LDL), progesterone, or estradiol-17β (E ₂ )-containing medium for 24 h. NP serum elevated H ₂ O ₂ levels via reducing catalase and glutathione peroxidase 1 levels, thereby enhancing K _Ca s levels via a H ₂ O ₂ /fyn/extracellular signal-regulated kinase (ERK)-mediated pathway. VEGF enhanced H ₂ O ₂ and K _Ca s levels and K _Ca 3.1 currents. K _Ca s were upregulated and K _Ca s activation-induced endothelium-dependent relaxation (EDR) was augmented in vessels from pregnant mice and rats. Whereas PE serum, ox-LDL, progesterone, or soluble fms-like tyrosine kinase 1 (sFlt-1) elevated superoxide levels via elevating NADPH oxidase 2 (NOX2) and NOX4 levels and reducing superoxide dismutase (SOD) 1 levels, thereby downregulating K _Ca s. sFlt-1 inhibited EDR. PE serum-or progesterone-induced alterations in levels of K _Ca s were reversed by polyethylene glycol-SOD, NOX inhibition, or E ₂ . Innovation and Conclusions: This is the first study of how endothelial K _Ca s levels are modulated during NP and PE. K _Ca s were upregulated by soluble serum factors such as VEGF via H ₂ O ₂ generation in NP, and were downregulated by serum factors such as progesterone and ox-LDL via superoxide generation in PE, which may contribute to hemodynamic adaptations in NP or to the development of PE.