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

• Published in: The FASEB journal Vol. 32; no. 5; p. 2574
• Main Authors: Sones, Jennifer L, Merriam, Audrey A, Seffens, Angelina, Brown-Grant, Dex-Ann, Butler, Scott D, Zhao, Anna M, Xu, Xinjing, Shawber, Carrie J, Grenier, Jennifer K, Douglas, Nataki C
• Format: Journal Article
• Language: English
• Published: United States 01.05.2018
• Subjects: Animals; Complement System Proteins - genetics; Complement System Proteins - metabolism; Decidua - blood supply; Decidua - metabolism; Decidua - pathology; Disease Models, Animal; Female; Gene Expression Regulation; Humans; Mice; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Pre-Eclampsia - genetics; Pre-Eclampsia - metabolism; Pre-Eclampsia - pathology; Pregnancy; Trophoblasts - metabolism; Trophoblasts - pathology; Vascular Endothelial Growth Factor A - biosynthesis; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor Receptor-1 - biosynthesis; Vascular Endothelial Growth Factor Receptor-1 - genetics; RGC32; implantation; trophoblast; sFlt-1; VEGF; decidual vasculature
• ISSN: 1530-6860
• DOI: 10.1096/fj.201701008R

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 VEGF 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 findings suggest that abnormal decidual angiogenesis precedes complement activation, which in turn contributes to the aberrant trophoblast invasion and poor placentation that underlie PE.-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. Angiogenic factor imbalance precedes complement deposition in placentae of the BPH/5 model of preeclampsia.