Angiogenic factor imbalance precedes complement deposition in placentae of the BPH/5 model of preeclampsia

Jennifer L. Sones, Audrey A. Merriam, Angelina Seffens, Dex Ann Brown-Grant, Scott D. Butler, Anna M. Zhao, Xinjing Xu, Carrie J. Shawber, Jennifer K. Grenier, Nataki C. Douglas

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Abstract

Preeclampsia (PE), a hypertensive disorder of pregnancy, is a leading cause of maternal and fetal morbidity and mortality. Although the etiology is unknown, PE is thought to be caused by defective implantation and decidualization in pregnancy. Pregnant blood pressure high (BPH)/5 mice spontaneously develop placentopathies and maternal features of human PE. We hypothesized that BPH/5 implantation sites have transcriptomic alterations. Next-generation RNA sequencing of implantation sites at peak decidualization, embryonic day (E)7.5, revealed complement gene up-regulation in BPH/5 vs. controls. In BPH/5, expression of complement factor 3 was increased around the decidual vasculature of E7.5 implantation sites and in the trophoblast giant cell layer of E10.5 placentae. Altered expression of VEGF pathway genes in E5.5 BPH/5 implantation sites preceded complement dysregulation, which correlated with abnormal vasculature and increased placental growth factor mRNA and VEGF164 expression at E7.5. By E10.5, proangiogenic genes were down-regulated, whereas antiangiogenic sFlt-1 was up-regulated in BPH/5 placentae. We found that early local misexpression of VEGF genes and abnormal decidual vasculature preceded sFlt-1 overexpression and increased complement deposition in BPH/5 placentae. Our finding ssuggest that abnormal decidual angiogenesis precedes complement activation, which in turn contributes to the aberrant tro-phoblast invasion and poor placentation that underlie PE.

Original languageEnglish (US)
Pages (from-to)2574-2586
Number of pages13
JournalFASEB Journal
Volume32
Issue number5
DOIs
StatePublished - May 2018

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All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Keywords

  • Decidual vasculature
  • Implantation
  • RGC32
  • SFlt-1
  • Trophoblast
  • VEGF

Cite this

Sones, J. L., Merriam, A. A., Seffens, A., Brown-Grant, D. A., Butler, S. D., Zhao, A. M., Xu, X., Shawber, C. J., Grenier, J. K., & Douglas, N. C. (2018). Angiogenic factor imbalance precedes complement deposition in placentae of the BPH/5 model of preeclampsia. FASEB Journal, 32(5), 2574-2586. https://doi.org/10.1096/fj.201701008R