Matin, Mahsa 
ORCID: 0000-0001-7954-6863
(2022).
Modulating angiogenic balance to establish novel treatment strategies and a disease model for preeclampsia.
PhD thesis, Universität zu Köln.
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Mahsa Matin Dissertation.pdf - Accepted Version Download (2MB) | Preview |
Abstract
Preeclampsia is a pregnancy-specific complication, occurring in 6 – 8 % of pregnancy cases, and is the leading cause of 76,000 maternal and 500,000 prenatal deaths per year worldwide (Redman and Sargent 2005). Due to the current lack of effective treatment options and its high prevalence, the development of novel and effective therapies for preeclampsia is of great importance ('Gestational Hypertension and Preeclampsia: ACOG Practice Bulletin Summary, Number 222' 2020). So far, there is no clear understanding of the pathophysiology of proteinuria and hypertension caused by preeclampsia, and animal models to study preeclampsia are debatable. Yet, it is well known that elevated sFlt-1 plasma levels, by scavenging VEGF and PlGF, lead to preeclampsia (Maynard et al. 2003; Levine et al. 2004). Pilot trials of apheresis therapy to eliminate sFlt-1 in patients with severe preeclampsia proved to be safe and effective (Thadhani et al. 2011). However, currently used platforms for sFlt-1 apheresis are unspecific, eliminating not only sFlt-1 but also other soluble proteins and factors. The current thesis establishes a highly specific sFlt-1 apheresis set up through the generation of a VEGF-based ligand with enhanced binding characteristics for sFlt-1. This novel ligand enables adsorption of up to 80% of circulating sFlt1 with the highest specificity while additionally restoring angiogenic balance by liberating endogenous PlGF and VEGF. According to in silico molecular modeling, a single-chain VEGF165 dimer (scVEGF165) was generated, which multimerizes to tetra- and higher multimeric VEGF molecules with enhanced sFlt-1 binding characteristics. A short peptide linker hampers intrachain dimerization scVEGF165 to induce assembly, preferably as tetrameric molecules as visualized in negative staining electron microscopy. scVEGF165 multimers possess a 1.2-fold higher affinity for sFlt-1 as compared to the available antibodies or monomeric VEGF. Consequently, scVEGF165 multimers have the ability to competitively release sFlt-1-bound PlGF and, in particular, VEGF. In ex vivo adsorption experiments using serum samples from patients with preeclampsia, scVEGF165 multimers reduce sFlt-1 levels by 85% and increase PlGF and VEGF levels by 20- and 9-fold, respectively. This system is directly applicable for further testing in large animal models of preeclampsia, which is crucial to evaluate the effect of VEGF release on pregnancy. Furthermore, in this thesis, a novel transgenic mouse model of preeclampsia that expresses soluble human sFlt-1, is characterized. Through inducible systemic expression of sFlt-1, hallmarks of preeclampsia, hypertension, and proteinuria are reproducible in this mouse model. The findings described in this thesis will help to create a highly effective, targeted apheresis therapy for patients with preeclampsia. In addition, the presented mouse model will be an important tool for studies enhancing our understanding of renal physiology and pathophysiology of preeclampsia.
| Item Type: | Thesis (PhD thesis) | ||||||||
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| URN: | urn:nbn:de:hbz:38-622186 | ||||||||
| Date: | 7 June 2022 | ||||||||
| Language: | English | ||||||||
| Faculty: | Faculty of Mathematics and Natural Sciences | ||||||||
| Divisions: | Zentrum für Molekulare Medizin | ||||||||
| Subjects: | Life sciences Medical sciences Medicine |
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| Date of oral exam: | 7 June 2022 | ||||||||
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| Refereed: | Yes | ||||||||
| URI: | http://kups.ub.uni-koeln.de/id/eprint/62218 |
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