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Reductions in βENaC and ASIC2 Induce Preeclampsia‐Like Symptoms in Pregnant Mice
Author(s) -
Warrington Junie Paula,
Granger Joey P,
Ryan Michael J,
Drummond Heather A
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1214.9
Subject(s) - epithelial sodium channel , preeclampsia , medicine , endocrinology , trophoblast , pregnancy , placenta , fetus , gestation , biology , chemistry , sodium , organic chemistry , genetics
Preeclampsia is a complex, multi‐organ, pregnancy‐specific condition characterized by new onset hypertension with or without proteinuria past the 20 th week of gestation. The underlying pathophysiological mechanisms have not been fully elucidated. Beta Epithelial Na + Channels (βENaC) and Acid Sensing Ion Channel 2 (ASIC2), members of the degenerin protein family, play important roles in vascular function including smooth muscle cell migration. We and others have shown that βENaC is also important for trophoblast migration. While βENaC is reduced in placentas from preeclampsia patients and a rat model of placental ischemia‐induced hypertension, it is not known whether reductions in degenerin proteins lead to altered placental function and cardiovascular abnormalities during pregnancy. Therefore, the purpose of this study was to determine if reductions in ASIC2 and βENaC contribute to preeclampsia‐like symptoms during pregnancy using a novel genetic mouse model initially generated by crossing ASIC2 null mice with mice with reduced levels of βENaC (βENaC m/m ) (ASIC2 −/− × βENaC m/m ). In this study, adult virgin female mice were mated with age‐ and genotype‐matched males overnight and separated the following morning (day of separation considered gestational day one). Mice were weighed every other day and on gestational day 18.5, tissues were harvested for analysis. Pregnant ASIC2 −/− × βENaC m/m mice gained significantly less weight during pregnancy (8.3 ± 0.7 vs. 14.0 ± 1.4g, p = 0.003), had increased fetal resorptions (29.1 ± 6.7 vs. 2.1 ± 2.1%, p = 0.002), and decreased number of live pups (3 ± 1 vs. 9 ± 1, p < 0.001) compared to wild‐type (WT) pregnant mice (n = 5–6 per genotype). However, both fetal (1.0 ± 0.1 vs. 0.8 ± 0.1g, p = 0.005) and placental (0.14 ± 0.00 vs 0.10 ± 0.01g, p < 0.001) weights were significantly higher in the pregnant ASIC2 −/− × βENaC m/m mice compared to WT pregnant group. Additionally, pregnant ASIC2 −/− × βENaC m/m mice had decreased circulating levels of vascular endothelial growth factor (VEGF; 122 ± 11 vs. 206 ± 22 pg/mL, p = 0.009) and modest elevations in blood pressure (113 ± 2 vs. 102 ± 4 mmHg, p = 0.02) compared to WT pregnant mice. These data indicate that pregnancy, superimposed on the ASIC2 −/− × βENaC m/m background, produces preeclampsia‐like symptoms. Future studies will assess the relative role of ASIC2 and βENaC in mediating these changes during pregnancy. Support or Funding Information NIH P20GM104357, P01HL051971, AHA 13POST16240000, and AHA20410022.