Alterations in the complement pathway in a mouse model of preeclampsia

Preeclampsia (PE) develops due to abnormal placentation. Complement, part of the innate immune system, is required for normal placental development. Abnormal complement activation has been shown in placenta and serum from women with PE and animal models of PE. Prior studies lack analyses at the time of placentation. We used a mouse model of PE, BPH/5, to characterize changes in complement at the maternal-fetal (MF) interface in early gestation. The BPH/5 mouse is the best known non-primate model to spontaneously develop PE-like disease. Timed matings were established to assess complement in the pregnant uterus prior to placentation at embryonic day (E) 7.5 and in placenta at E10.5. We used quantitative (q) RT-PCR to assess mRNA expression of the following genes: complement 1 (C1); complement 3 (C3), the common point of the complement pathway; Ptgs, marker of decidualization; Flt-1 and sFlt-1, angiogenic genes altered in PE. To assess C3 deposition, we performed immunofluorescence (IF) on frozen sections (4 independent samples) with antibodies against C3. To quantify C3 deposition, corrected total cell fluorescence (CTCF) was measured using Image J software. At E7.5, increased Ptgs expression in BPH/5 mice is consistent with abnormal decidualization (Figure 1). Similarly, C3 expression and deposition at the mesometrial pole where the placenta develops were increased in BPH/5 mice at E7.5 (Figures 1 and 2). Mean C3 CTCF in decidual vasculature was significantly higher in BPH/5 mice compared to controls (27.09 v. 4.97, P< 0.05). In the placenta at E10.5, C3 expression was significantly increased in BPH/5 mice. Placental expression of sFlt-1 was also significantly increased, suggestive of abnormal placental angiogenesis seen in PE (Figure 1). In BPH/5 mice, C3 expression and deposition are increased at the MF interface in the uterus pre-placentation and in the placenta. These findings early in gestation implicate abnormal complement activation in the pathogenesis of PE.View Large Image Figure ViewerDownload Hi-res image Download (PPT)