Heme oxygenase-1 promotes migration and β-epithelial Na+ channel expression in cytotrophoblasts and ischemic placentas

Junie P. Warrington, Kayla Coleman, Courtney Skaggs, Peter Hosick, Eric M. George, David E. Stec, Michael J. Ryan, Joey P. Granger, Heather A. Drummond

Research output: Contribution to journalArticleResearchpeer-review

5 Citations (Scopus)

Abstract

Preeclampsia is thought to arise from inadequate cytotrophoblast migration and invasion of the maternal spiral arteries, resulting in placental ischemia and hypertension. Evidence suggests that altered expression of epithelial Na+ channel (ENaC) proteins may be a contributing mechanism for impaired cytotrophoblast migration. ENaC activity is required for normal cytotrophoblast migration. Moreover, β-ENaC, the most robustly expressed placental ENaC message, is reduced in placentas from preeclamptic women. We recently demonstrated that heme oxygenase-1 (HO-1) protects against hypertension in a rat model of placental ischemia; however, whether HO-1 regulation of β-ENaC contributes to the beneficial effects of HO-1 is unknown. The purpose of this study was to determine whether β-ENaC mediates cytotrophoblast migration and whether HO-1 enhances ENaC-mediated migration. We showed that placental ischemia, induced by reducing uterine perfusion suppressed, and HO-1 induction restored, β-ENaC expression in ischemic placentas. Using an in vitro model, we found that HO-1 induction, using cobalt protoporphyrin, stimulates cytotrophoblast β-ENaC expression by 1.5- and 1.8-fold (10 and 50 μM). We then showed that silencing of β-ENaC in cultured cytotrophoblasts (BeWo cells), by expression of dominant-negative constructs, reduced migration to 56 ± 13% (P < 0.05) of control. Importantly, HO-1 induction enhanced migration (43 ± 5% of control, P < 0.05), but the enhanced migratory response was entirely blocked by ENaC inhibition with amiloride (10 μM). Taken together, our results suggest that β-ENaC mediates cytotrophoblast migration and increasing β-ENaC expression by HO-1 induction enhances migration. HO-1 regulation of cytotrophoblast β-ENaC expression and migration may be a potential therapeutic target in preeclamptic patients.

Original languageEnglish
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume306
Issue number9
DOIs
StatePublished - 1 May 2014

Fingerprint

Epithelial Sodium Channels
Heme Oxygenase-1
Trophoblasts
Placenta
Ischemia
Hypertension
Amiloride
Pre-Eclampsia

Keywords

  • Cytotrophoblast
  • Heme oxygenase-1
  • Placenta
  • Preeclampsia
  • β-ENaC

Cite this

Warrington, Junie P. ; Coleman, Kayla ; Skaggs, Courtney ; Hosick, Peter ; George, Eric M. ; Stec, David E. ; Ryan, Michael J. ; Granger, Joey P. ; Drummond, Heather A. / Heme oxygenase-1 promotes migration and β-epithelial Na+ channel expression in cytotrophoblasts and ischemic placentas. In: American Journal of Physiology - Regulatory Integrative and Comparative Physiology. 2014 ; Vol. 306, No. 9.
@article{1cc6410ddd914dddaf2b9f0c98438bfc,
title = "Heme oxygenase-1 promotes migration and β-epithelial Na+ channel expression in cytotrophoblasts and ischemic placentas",
abstract = "Preeclampsia is thought to arise from inadequate cytotrophoblast migration and invasion of the maternal spiral arteries, resulting in placental ischemia and hypertension. Evidence suggests that altered expression of epithelial Na+ channel (ENaC) proteins may be a contributing mechanism for impaired cytotrophoblast migration. ENaC activity is required for normal cytotrophoblast migration. Moreover, β-ENaC, the most robustly expressed placental ENaC message, is reduced in placentas from preeclamptic women. We recently demonstrated that heme oxygenase-1 (HO-1) protects against hypertension in a rat model of placental ischemia; however, whether HO-1 regulation of β-ENaC contributes to the beneficial effects of HO-1 is unknown. The purpose of this study was to determine whether β-ENaC mediates cytotrophoblast migration and whether HO-1 enhances ENaC-mediated migration. We showed that placental ischemia, induced by reducing uterine perfusion suppressed, and HO-1 induction restored, β-ENaC expression in ischemic placentas. Using an in vitro model, we found that HO-1 induction, using cobalt protoporphyrin, stimulates cytotrophoblast β-ENaC expression by 1.5- and 1.8-fold (10 and 50 μM). We then showed that silencing of β-ENaC in cultured cytotrophoblasts (BeWo cells), by expression of dominant-negative constructs, reduced migration to 56 ± 13{\%} (P < 0.05) of control. Importantly, HO-1 induction enhanced migration (43 ± 5{\%} of control, P < 0.05), but the enhanced migratory response was entirely blocked by ENaC inhibition with amiloride (10 μM). Taken together, our results suggest that β-ENaC mediates cytotrophoblast migration and increasing β-ENaC expression by HO-1 induction enhances migration. HO-1 regulation of cytotrophoblast β-ENaC expression and migration may be a potential therapeutic target in preeclamptic patients.",
keywords = "Cytotrophoblast, Heme oxygenase-1, Placenta, Preeclampsia, β-ENaC",
author = "Warrington, {Junie P.} and Kayla Coleman and Courtney Skaggs and Peter Hosick and George, {Eric M.} and Stec, {David E.} and Ryan, {Michael J.} and Granger, {Joey P.} and Drummond, {Heather A.}",
year = "2014",
month = "5",
day = "1",
doi = "10.1152/ajpregu.00566.2013",
language = "English",
volume = "306",
journal = "American Journal of Physiology - Regulatory Integrative and Comparative Physiology",
issn = "0363-6119",
publisher = "American Physiological Society",
number = "9",

}

Heme oxygenase-1 promotes migration and β-epithelial Na+ channel expression in cytotrophoblasts and ischemic placentas. / Warrington, Junie P.; Coleman, Kayla; Skaggs, Courtney; Hosick, Peter; George, Eric M.; Stec, David E.; Ryan, Michael J.; Granger, Joey P.; Drummond, Heather A.

In: American Journal of Physiology - Regulatory Integrative and Comparative Physiology, Vol. 306, No. 9, 01.05.2014.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Heme oxygenase-1 promotes migration and β-epithelial Na+ channel expression in cytotrophoblasts and ischemic placentas

AU - Warrington, Junie P.

AU - Coleman, Kayla

AU - Skaggs, Courtney

AU - Hosick, Peter

AU - George, Eric M.

AU - Stec, David E.

AU - Ryan, Michael J.

AU - Granger, Joey P.

AU - Drummond, Heather A.

PY - 2014/5/1

Y1 - 2014/5/1

N2 - Preeclampsia is thought to arise from inadequate cytotrophoblast migration and invasion of the maternal spiral arteries, resulting in placental ischemia and hypertension. Evidence suggests that altered expression of epithelial Na+ channel (ENaC) proteins may be a contributing mechanism for impaired cytotrophoblast migration. ENaC activity is required for normal cytotrophoblast migration. Moreover, β-ENaC, the most robustly expressed placental ENaC message, is reduced in placentas from preeclamptic women. We recently demonstrated that heme oxygenase-1 (HO-1) protects against hypertension in a rat model of placental ischemia; however, whether HO-1 regulation of β-ENaC contributes to the beneficial effects of HO-1 is unknown. The purpose of this study was to determine whether β-ENaC mediates cytotrophoblast migration and whether HO-1 enhances ENaC-mediated migration. We showed that placental ischemia, induced by reducing uterine perfusion suppressed, and HO-1 induction restored, β-ENaC expression in ischemic placentas. Using an in vitro model, we found that HO-1 induction, using cobalt protoporphyrin, stimulates cytotrophoblast β-ENaC expression by 1.5- and 1.8-fold (10 and 50 μM). We then showed that silencing of β-ENaC in cultured cytotrophoblasts (BeWo cells), by expression of dominant-negative constructs, reduced migration to 56 ± 13% (P < 0.05) of control. Importantly, HO-1 induction enhanced migration (43 ± 5% of control, P < 0.05), but the enhanced migratory response was entirely blocked by ENaC inhibition with amiloride (10 μM). Taken together, our results suggest that β-ENaC mediates cytotrophoblast migration and increasing β-ENaC expression by HO-1 induction enhances migration. HO-1 regulation of cytotrophoblast β-ENaC expression and migration may be a potential therapeutic target in preeclamptic patients.

AB - Preeclampsia is thought to arise from inadequate cytotrophoblast migration and invasion of the maternal spiral arteries, resulting in placental ischemia and hypertension. Evidence suggests that altered expression of epithelial Na+ channel (ENaC) proteins may be a contributing mechanism for impaired cytotrophoblast migration. ENaC activity is required for normal cytotrophoblast migration. Moreover, β-ENaC, the most robustly expressed placental ENaC message, is reduced in placentas from preeclamptic women. We recently demonstrated that heme oxygenase-1 (HO-1) protects against hypertension in a rat model of placental ischemia; however, whether HO-1 regulation of β-ENaC contributes to the beneficial effects of HO-1 is unknown. The purpose of this study was to determine whether β-ENaC mediates cytotrophoblast migration and whether HO-1 enhances ENaC-mediated migration. We showed that placental ischemia, induced by reducing uterine perfusion suppressed, and HO-1 induction restored, β-ENaC expression in ischemic placentas. Using an in vitro model, we found that HO-1 induction, using cobalt protoporphyrin, stimulates cytotrophoblast β-ENaC expression by 1.5- and 1.8-fold (10 and 50 μM). We then showed that silencing of β-ENaC in cultured cytotrophoblasts (BeWo cells), by expression of dominant-negative constructs, reduced migration to 56 ± 13% (P < 0.05) of control. Importantly, HO-1 induction enhanced migration (43 ± 5% of control, P < 0.05), but the enhanced migratory response was entirely blocked by ENaC inhibition with amiloride (10 μM). Taken together, our results suggest that β-ENaC mediates cytotrophoblast migration and increasing β-ENaC expression by HO-1 induction enhances migration. HO-1 regulation of cytotrophoblast β-ENaC expression and migration may be a potential therapeutic target in preeclamptic patients.

KW - Cytotrophoblast

KW - Heme oxygenase-1

KW - Placenta

KW - Preeclampsia

KW - β-ENaC

UR - http://www.scopus.com/inward/record.url?scp=84900543672&partnerID=8YFLogxK

U2 - 10.1152/ajpregu.00566.2013

DO - 10.1152/ajpregu.00566.2013

M3 - Article

VL - 306

JO - American Journal of Physiology - Regulatory Integrative and Comparative Physiology

JF - American Journal of Physiology - Regulatory Integrative and Comparative Physiology

SN - 0363-6119

IS - 9

ER -