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.
authors.affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi.
authors.forename: Junie P
authors.initials: JP
authors.lastname: Warrington
authors.forename: Kayla
authors.initials: K
authors.lastname: Coleman
authors.forename: Courtney
authors.initials: C
authors.lastname: Skaggs
authors.forename: Peter A
authors.initials: PA
authors.lastname: Hosick
authors.forename: Eric M
authors.initials: EM
authors.lastname: George
authors.forename: David E
authors.initials: DE
authors.lastname: Stec
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ryan
authors.forename: Joey P
authors.initials: JP
authors.lastname: Granger
authors.forename: Heather A
authors.initials: HA
authors.lastname: Drummond
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D004195:Disease Models, Animal; D004790:Enzyme Induction; D053503:Epithelial Sodium Channels / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D007511:Ischemia / Q000201:enzymology* / Q000503:physiopathology; D010920:Placenta / Q000098:blood supply* / Q000201:enzymology*; D021041:Placental Circulation; D011225:Pre-Eclampsia / Q000378:metabolism / Q000503:physiopathology; D011247:Pregnancy; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014162:Transfection; D014327:Trophoblasts / Q000201:enzymology*
chemical_list: D053503:Epithelial Sodium Channels; C507048:SCNN1B protein, human; C507050:Scnn1b protein, rat; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C491523:Hmox1 protein, rat
keywords: cytotrophoblast; heme oxygenase-1; placenta; preeclampsia; β-ENaC