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///2017 Abstract Details
2017 Abstract Details2019-08-02T15:54:53-05:00

CSF protein signature in preeclampsia converges on TGF-beta, VEGFA, AGT, and IL-6 signaling pathways

Abstract Number: O-03
Abstract Type: Original Research

Erin J Ciampa MD, PhD1 ; Towia Libermann PhD2; Laura Sorabella MD3; Yunping Li MD4; S. Ananth Karumanchi MD5; Philip Hess MD6

Introduction: A wide range of pathological changes at the molecular level can be postulated to explain the heightened excitability, visual changes, headache, and seizure susceptibility that can occur in preeclampsia (PE). We know that dysregulated endothelial signaling, vascular remodeling and widespread inflammation are principal contributors to the pathogenesis of systemic features of PE [1, 2], but scarce data have implicated these pathways or any others specifically in the development of its central nervous system (CNS) manifestations. In this study, we analyzed the relationships of signaling molecules that emerged from a proteomics screen comparing the cerebrospinal fluid (CSF) protein content of patients with PE to normal controls.

Methods: Based on results of a SOMAscan aptamer-based array of CSF proteins, we performed Ingenuity Pathway Analysis to highlight relationships between target proteins found to be significantly up- or down-regulated in PE. For two members of the TGF-beta pathway, INHBA and FSTL3 (also known as Activin A and FLRG, respectively), we validated the difference in protein concentration between groups by ELISA, using commercially available kits (Ansh Labs; R&D Systems). Mean concentrations and SEM were calculated and unpaired student t-test was applied to determine statistical significance of the differences between groups.

Results: The differentially expressed proteins showed significant convergence around four signaling molecules (Figure 1A): transforming growth factor beta (TGF-beta), vascular endothelial growth factor A (VEGFA), angiotensinogen (AGT), and interleukin 6 (IL-6). Within the TGF-beta pathway, upregulation of Activin A (301.6 ± 47.4 pg/mL versus 151.6 ± 20.5 pg/mL, p = 0.0074) and FLRG (5129 ± 347 pg/mL versus 3016 ± 188 pg/mL, p < 0.0001) in PE was confirmed by ELISA (Figure 1B).

Conclusions: Signaling pathways important for vascular remodeling, neuronal survival, and inflammation were well represented among the proteins found to have altered expression levels in CSF in patients with PE. Future work will help determine which changes reflect primary insults versus collateral damage and compensatory modulation. With a clear understanding of the pathogenic mechanisms underlying the CNS manifestations of PE, we can hope to achieve better treatment and prevention of these potentially devastating clinical outcomes.

References:

1. Nat Med, 2006. 12(6): p. 642-9.

2. J Clin Invest, 2016. 126(7): p. 2561-74.



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