Altered Redox State Modulates Endothelial K Ca 2.3 and K Ca 3.1 Levels in Normal Pregnancy and Preeclampsia

Abstract

Aims:

Altered redox state has been related to the development of normal pregnancy (NP) and preeclampsia (PE). Endothelial K_Ca2.3 and K_Ca3.1 (K_Cas) play an important role in vasodilation, and K_Cas levels are affected by oxidative stress. We investigated the mechanisms of oxidative stress-mediated K_Cas 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 (E₂)-containing medium for 24 h. NP serum elevated H₂O₂ levels via reducing catalase and glutathione peroxidase 1 levels, thereby enhancing K_Cas levels via a H₂O₂/fyn/extracellular signal-regulated kinase (ERK)-mediated pathway. VEGF enhanced H₂O₂ and K_Cas levels and K_Ca3.1 currents. K_Cas were upregulated and K_Cas 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_Cas. sFlt-1 inhibited EDR. PE serum- or progesterone-induced alterations in levels of K_Cas were reversed by polyethylene glycol-SOD, NOX inhibition, or E₂.

Innovation and Conclusions:

This is the first study of how endothelial K_Cas levels are modulated during NP and PE. K_Cas were upregulated by soluble serum factors such as VEGF via H₂O₂ 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.