Altered redox state modulates endothelial KCa2.3 and KCa3.1 levels in normal pregnancy and preeclampsia

Shinkyu Choi, Ji Aee Kim, Hai Yan Li, Sae Jin Lee, Ye Seon Seok, Tae Hun Kim, Ki Hwan Han, Mi Hye Park, Geum-Joon Cho, Suk Hyo Suh

Research output: Contribution to journalArticle

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Abstract

Aims: 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. 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 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.

Original languageEnglish
Pages (from-to)505-519
Number of pages15
JournalAntioxidants and Redox Signaling
Volume30
Issue number4
DOIs
Publication statusPublished - 2019 Jan 1

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Pre-Eclampsia
Oxidation-Reduction
Progesterone
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factor Receptor-1
Pregnancy
Oxidative stress
Superoxides
Serum
NADPH Oxidase
Extracellular Signal-Regulated MAP Kinases
Endothelial cells
Hemodynamics
Catalase
Superoxide Dismutase
Endothelium
Rats
Estradiol
Oxidative Stress
Down-Regulation

Keywords

  • Ca-activated K channels
  • endothelial cells
  • preeclampsia
  • pregnancy
  • redox state

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

Cite this

Altered redox state modulates endothelial KCa2.3 and KCa3.1 levels in normal pregnancy and preeclampsia. / Choi, Shinkyu; Kim, Ji Aee; Li, Hai Yan; Lee, Sae Jin; Seok, Ye Seon; Kim, Tae Hun; Han, Ki Hwan; Park, Mi Hye; Cho, Geum-Joon; Suh, Suk Hyo.

In: Antioxidants and Redox Signaling, Vol. 30, No. 4, 01.01.2019, p. 505-519.

Research output: Contribution to journalArticle

Choi, S, Kim, JA, Li, HY, Lee, SJ, Seok, YS, Kim, TH, Han, KH, Park, MH, Cho, G-J & Suh, SH 2019, 'Altered redox state modulates endothelial KCa2.3 and KCa3.1 levels in normal pregnancy and preeclampsia', Antioxidants and Redox Signaling, vol. 30, no. 4, pp. 505-519. https://doi.org/10.1089/ars.2017.7038
Choi, Shinkyu ; Kim, Ji Aee ; Li, Hai Yan ; Lee, Sae Jin ; Seok, Ye Seon ; Kim, Tae Hun ; Han, Ki Hwan ; Park, Mi Hye ; Cho, Geum-Joon ; Suh, Suk Hyo. / Altered redox state modulates endothelial KCa2.3 and KCa3.1 levels in normal pregnancy and preeclampsia. In: Antioxidants and Redox Signaling. 2019 ; Vol. 30, No. 4. pp. 505-519.
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AU - Kim, Ji Aee

AU - Li, Hai Yan

AU - Lee, Sae Jin

AU - Seok, Ye Seon

AU - Kim, Tae Hun

AU - Han, Ki Hwan

AU - Park, Mi Hye

AU - Cho, Geum-Joon

AU - Suh, Suk Hyo

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N2 - Aims: 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. 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 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.

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