Altered Redox State Modulates Endothelial KCa2.3 and KCa3.1 Levels in Normal Pregnancy and Preeclampsia

Altered redox state has been related to the development of normal pregnancy (NP) and preeclampsia (PE). Endothelial KCa2.3 and KCa3.1 (KCas) play an important role in vasodilation, and KCas levels are affected by oxidative stress. We investigated the mechanisms of oxidative stress-mediated KCas expression modulation during NP and PE.

This is the first study of how endothelial KCas levels are modulated during NP and PE. KCas 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.

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 KCas levels via a H2O2/fyn/extracellular signal-regulated kinase (ERK)-mediated pathway. VEGF enhanced H2O2 and KCas levels and KCa3.1 currents. KCas were upregulated and KCas 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 KCas. sFlt-1 inhibited EDR. PE serum- or progesterone-induced alterations in levels of KCas were reversed by polyethylene glycol-SOD, NOX inhibition, or E2. Innovation and Conclusions: This is the first study of how endothelial KCas levels are modulated during NP and PE. KCas 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.