Abstract 281: HO-1 Induction Increases ßENaC in Ischemic Placentas and Cultured Cytotrophoblasts

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Abstract

Preeclampsia is characterized by abnormal placentation that is thought to arise from inadequate cytotrophoblast migration and invasion of the spiral arteries. The resulting reduced perfusion of the utero-placental unit promotes the development of hypertension in preeclampsia. Beta Epithelial Na+ Channel (βENaC) protein, a mediator of cytotrophoblast migration in vitro, is decreased in placentas of preeclamptic patients. We have recently reported that hemeoxygenase-1 (HO-1) and its by-products reduce blood pressure in placental ischemic rats. Since HO and its byproducts can regulate ENaC expression, including βENaC, are important mediators of migration, the goal of this study was to test the hypothesis that HO-1 induction 1) stimulates βENaC expression and migration in cultured cytotrophoblasts and 2) restores βENaC expression in ischemic placentas. Cobalt protoporhyrin (CoPP, 1 - 10 μM, 48 hrs) stimulated HO-1 induction in cultured cytotrophoblasts (BEWO cells), upregulated βENaC expression, and increased spontaneous migration by 39.2 ± 6.0% (n=7, p<0.001). To determine if HO-1 induction increased placental βENaC expression and prevented hypertension, CoPP was injected subcutaneously (5mg/kg) on gestational day 14 in timed pregnant Sprague-Dawley rats with placental ischemia. MAP was increased on gestational day 19 in placental ischemic rats (141 ± 4 vs.101 ± 1 mmHg, p<0.001; n=4 per group). While HO-1 induction did not affect MAP in normal pregnant rats (101 ± 5 mmHg), MAP was significantly attenuated (p<0.01) in placental ischemic rats treated with CoPP (117 ± 1 mmHg). Western blot analysis revealed a 62 ± 22% decrease in βENaC expression in ischemic placentas, which was restored by HO-1 induction (n= 4, p<0.05). These findings suggest that HO-1 induction stimulates βENaC expression in cultured cytotrophoblasts and ischemic placentas. Future studies will determine if the beneficial effects of HO-1 occur through βENaC-mediated cytotrophoblast migration and spiral artery remodeling in ischemic placentas. Targeting the HO-1 pathway presents a potential therapeutic approach for improving placentation in preeclamptic women.

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