Angiogenic factor imbalance precedes complement deposition in the placenta of preeclamptic-like BPH/5 mice
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ABSTRACT: BPH/5 mice are an inbred strain with “borderline hypertension” that spontaneously develops both maternal and fetal hallmarks of preeclampsia. RNA-Seq analysis of BPH/5 uterine implantation sites at embryonic day 7.5, the peak of decidualization, identifies differential expression of inflammatory response genes, including members of the complement family, compared to C57 controls.
Project description: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 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.
Project description:Transcriptome analysis of BPH-resistant and BPH-susceptible rice seedlings in response to BPH infestation. RH vs. 02428: a microarray analysis of genes that were differentially expressed in a BPH-resistant cultivar, Rathu Heenati (RH) and a susceptible cultivar 02428 after infestation with BPH for 24h. RB vs. SB: a microarray analysis of genes that were differentially expressed in resistant seedling pool and susceptible seedling pool both infested with BPH for 24h. RB vs. RN: a microarray analysis of genes that were differentially expressed in resistant seedling pool infested with BPH for 24h and resistant seedling pool without BPH infestation. Goal was to explore the molecular basis underlying BPH-resistance in rice.
Project description:We identified a BPH transcriptional signature that included 392 significantly differential expressed genes between BPH and control samples, and validated this BPH transcriptional signature using two independent study cohorts. By performing integrative analysis using transcriptional and methylation profiling, we identified two distinct BPH subtypes, supporting robust biologically distinct subgroups across different data types. To validate these BPH subtypes, we tested our signature via k-means clustering in two independent cohorts, and identified nearly identical subgroups. To nominate potential subtype specific therapeutic options, we utilized a Connectivity Map analysis, and found 50% of nominated compounds in one subgroup were related to inhibition of mTOR signaling.
Project description:Preeclampsia (PE) is a serious hypertensive disorder of pregnancy characterized by abnormal placental development with an unknown etiology. To better understand which women will develop PE, a number of maternal risk factors have been identified, including obesity. Visceral white adipose tissue (WAT) contains inflammatory mediators that may contribute to PE. To explore this, we utilized the blood pressure high (BPH)/5 mouse model of superimposed PE that spontaneously recapitulates the maternal PE syndrome. We hypothesized that BPH/5 visceral WAT adjacent to the female reproductive tract (reproductive WAT) is a source of complement factors that contribute to the inflammatory milieu and angiogenic imbalance at the maternal-fetal interface in this model and in preeclamptic women. To test our hypothesis, we calorie-restricted BPH/5 females for two weeks prior to pregnancy and the first seven days of pregnancy, which attenuated complement component 3 (C3) but not complement factor B, nor complement factor D, (adipsin) in the reproductive WAT or the implantation site in BPH/5. Furthermore, calorie restriction during pregnancy restored vascular endothelial and placental growth factor mRNA levels in the BPH/5 implantation site. These data show maternal reproductive WAT may be a source of increased C3 during pregnancy, which is increased at the maternal-fetal interface in preeclamptic BPH/5 mice. It also suggests that calorie restriction could regulate inflammatory mediators thought to contribute to placental dysfunction in PE. Future studies are necessary to examine the effect of calorie restriction on C3 throughout pregnancy and the role of maternal obesity in PE.
Project description:Single-cell mRNA sequencing (scRNA-seq) study was conducted to to probe heterogeneity of human BPH associated cells. No cell sorting was conducted so all cells within the BPH environment could be represented.
Project description:used to identify differences between tissues from patients undergoing surgery for BPH with unresolved symptoms compared to incidental BPH from patients with prostate cancer