Abstract
Elevated arginine vasopressin (AVP) is predictive of human preeclampsia (PreE) and causes a PreE phenotype in mice. Betamethasone (BMTZ), a corticosteroid administered to prevent preterm birth complications, inhibits AVP and stimulates serum/glucocorticoid regulated kinase 1 (SGK1), a serine/threonine kinase. In the AVP mouse model of PreE, early administration of BMTZ prevents preeclampsia. The objective of this study was to determine if BMTZ acts through SGK1 to inhibit the effects of AVP on trophoblast cell migration. Trophoblast migration was assessed using a human extravillous trophoblast cell line HTR-8/SVneo. Cells were plated into ibidi 2-well silicone inserts and allowed to adhere for 24 hours before removal of the insert creating a 500mm gap for migration analysis and treatment. Cells were treated with saline (n=7), AVP (n=7), AVP + BMTZ (n=3), or AVP + BMTZ + SGK1 inhibitor (n=3). Images were taken at 0 and 24 hours post-treatment. All wells were set up in duplicate and averaged for n=1. The area of the gap was measured and the percent closure for cell migration was calculated. Two-tailed Student t test or one way ANOVA multiple comparisons were performed with alpha=0.05. AVP treatment of trophoblast cells inhibited migration at 24 hours (Saline: 38% vs AVP: 25%, n=7 p< 0.05). Treatment of trophoblast cells with BMTZ prevented AVP induced inhibition of trophoblast migration (AVP: 25% n=7 vs AVP + BMTZ: 40% n=3, p< 0.05) with migration rates comparable to saline-treated cells (saline: 38% n=7 vs AVP + BMTZ: 40% n=3, p=0.99). The effect of BMTZ on AVP-induced inhibition of trophoblast cell migration was not mediated via SGK1 (AVP + BMTZ: 40% vs AVP + BMTZ + SGK1 inhibitor: 49%, n=3, p=0.51). These data demonstrate that AVP may play a role in placental dysfunction via inhibition of trophoblast migration. While BMTZ is sufficient to prevent the impaired trophoblast migration via AVP, these effects are mediated through a SGK1 independent mechanism.
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