Increased signaling of various hormones through their cognate G Protein-Coupled Receptors (GPCRs), including the angiotensin, endothelin, and vasopressin systems, are implicated in human preeclampsia (PreE) and animal models of the disorder. Cascade-specific termination of GPCR signaling following receptor activation is catalyzed by the Regulator of G protein Signaling (RGS) family members. Within the RGS B/R4 family, RGS5 and RGS2 are implicated in human PreE and gestational hypertensive disorders. Mutations within the RGS2 gene, a B/R4 RGS member, are associated with human hypertensive populations and increased risk of developing PreE and its sequelae. Given the role for the placenta in the pathogenesis of PreE, we hypothesized a role for RGS2 in the placenta during PreE.
My studies showed RGS2 mRNA expression is reduced in placentas from pregnancies affected by PreE. Reduced fetal-placental Rgs2 induces gestational hypertension, proteinuria, and increased plasma ALT activity in wildtype dams. Placentas with reduced Rgs2 expression exhibit reduced vascularization, increased thickness of the labyrinth and spongiotrophoblast layers, and enrichment for pathways associated with human PreE. Analysis of human PreE placenta samples reveals an increase in the cAMP/CREB signaling pathway, yet we demonstrate loss of CREB occupancy at the RGS2 promoter. HTR8 cell cultures indicate HDAC activity may be required CREB transcription of specific gene sets. In silico analysis supports this concept and further implies it may be impaired in human PreE placentas.
These findings demonstrate heterozygous loss of fetal-placental Rgs2 is sufficient to induce PreE phenotypes in wildtype dams during pregnancy. Additionally, they highlight the role of the placenta in maternal pathogenesis of PreE and support the concept that paternal genetics influence the risk of developing PreE.
| Identifer | oai:union.ndltd.org:uiowa.edu/oai:ir.uiowa.edu:etd-8120 |
| Date | 01 December 2018 |
| Creators | Perschbacher, Katherine |
| Contributors | Grobe, Justin L. |
| Publisher | University of Iowa |
| Source Sets | University of Iowa |
| Language | English |
| Detected Language | English |
| Type | dissertation |
| Format | application/pdf |
| Source | Theses and Dissertations |
| Rights | Copyright © 2018 Katherine Perschbacher |
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