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

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

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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
Pages (from-to)R641-R646
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume306
Issue number9
DOIs
Publication statusPublished - 1 May 2014

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Keywords

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

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