Abstract 021: Betamethasone Prevents Preeclamptic Phenotypes By Upregulating Regulator Of G Protein Signaling 2

Abstract

Preeclampsia (PreE), a prevalent gestational disorder, is characterized by high blood pressure and kidney damage. Currently, the only known treatment for PreE is to deliver the baby. Chronic infusion of AVP in mice has been shown to recapitulate clinical symptoms of preeclampsia including pregnancy-specific hypertension. Corticosteroids are commonly given during pregnancy to promote fetal lung development. However, it is not known whether they can be used to manage PreE. C57Bl6/J mice received 24ng/hr of AVP throughout gestation until necropsy on gestational day 18. Betamethasone, a steroid, was administered at gestational day 7. An increase of 8.093 mmHg (110.72 vs 118.81, p=0.01) in systolic blood pressure was observed in AVP-infused mice compared to saline-infused pregnant mice and addition of BMTZ in AVP-infused mice returned blood pressure to baseline (109.59 mmHg, p=0.030). AVP treated mice had elevated expression of renal collagen 1A (4.99 fold, p=0.01) and TGFβ (2.58 fold, p=0.009) compared to saline infused mice. BMTZ reversed renal collagen 1A (0.98 fold, p=0.03) and TGFβ (0.75 fold, p=0.004) compared to AVP only infused mice. Trophoblast invasion of the uterine spiral arteries early in pregnancy is abnormal in women who develop PreE resulting in poor placental profusion. HTR8, a placental trophoblast cell, was treated with AVP or the combination of AVP and BMTZ. AVP decreased trophoblast migration by 34 units (p<0.001) and BMTZ rescued migration by 42.1 units (p<0.001). Similarly, AVP treatment decreased trophoblast invasion (0.58 vs 0.49 units, p=0.11) and BMTZ rescued invasion (0.62 units vs 0.49 units, p=0.032). Previously published data demonstrated that Regulator of G Protein Signaling 2 (RGS2) is decreased in placentas of PreE patients and RGS2 decreases AVP signaling. Trophoblasts treated with AVP show a 0.49 fold decrease in RGS2 expression and BMTZ rescues RGS2 expression (1.29 fold, p=0.038). Overexpression of RGS2 in AVP treated cells resulted in a 20 unit increase in migration (248.7 vs 268.7, p=0.01). These data demonstrate that BMTZ can prevent PreE phenotypes as well as abnormal trophoblast invasion and migration caused by AVP. RGS2 regulation by BMTZ may be the mechanism by which BMTZ is protective in preclinical models of PreE.