Universität zu Köln

Matin, Mahsa, Morgelin, Matthias, Stetefeld, Jorg, Schermer, Bernhard, Brinkkoetter, Paul T., Benzing, Thomas, Koch, Manuel and Hagmann, Henning (2020). Affinity-Enhanced Multimeric VEGF (Vascular Endothelial Growth Factor) and PlGF (Placental Growth Factor) Variants for Specific Adsorption of sFlt-1 to Restore Angiogenic Balance in Preeclampsia. Hypertension, 76 (4). S. 1176 - 1185. PHILADELPHIA: LIPPINCOTT WILLIAMS & WILKINS. ISSN 1524-4563

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Abstract

Preeclampsia is a potentially life-threatening multisystem disease affecting 4% to 8% of pregnant women after the 20th week of gestation. An excess of placental expressed antiangiogenic soluble VEGF (vascular endothelial growth factor)-receptor 1 (soluble FMS-like tyrosine kinase 1) scavenges VEGF and PlGF (placental growth factor), causing generalized endothelial dysfunction. Interventions to restore the angiogenic balance in preeclamptic pregnancies are intensively studied and improve maternal and neonatal outcomes. Especially extracorporeal strategies to remove sFlt-1 are promising in human pregnancy. However, available apheresis systems adsorb sFlt-1 unspecifically and with low efficiency. Affinity-enhanced ligands are needed to improve performance and compatibility of apheresis treatments. Using computerized molecular modeling, we developed multimeric VEGF molecules comprised of single-chain VEGF(165)dimers (scVEGF(165)). A short peptide linker hampers intrachain dimerization to induce assembly preferably as tetrameric molecules as visualized in negative staining electron microscopy. scVEGF(165)multimers possess 1.2-fold higher affinity for sFlt-1 as compared to the available antibodies or monomeric VEGF. Consequently, scVEGF 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, scVEGF multimers reduce sFlt-1 levels by 85% and increase PlGF and VEGF levels by 20- and 9-fold, respectively. Finally, performance and stability of sFlt-1 capturing scVEGF(165)multimers were scrutinized on different matrices of which biocompatible agarose matrix yielded optimal results. We introduce the first VEGF-based highly efficient sFlt-1 apheresis system that is directly applicable in vivo due to utilization of inert agarose matrix, using a homomultimeric form of VEGF(165)to restore the angiogenic balance in preeclampsia.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Matin, Mahsa UNSPECIFIED UNSPECIFIED UNSPECIFIED Morgelin, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Stetefeld, Jorg UNSPECIFIED UNSPECIFIED UNSPECIFIED Schermer, Bernhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Brinkkoetter, Paul T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Benzing, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Koch, Manuel UNSPECIFIED UNSPECIFIED UNSPECIFIED Hagmann, Henning UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-317676
DOI:	10.1161/HYPERTENSIONAHA.120.14974
Journal or Publication Title:	Hypertension
Volume:	76
Number:	4
Page Range:	S. 1176 - 1185
Date:	2020
Publisher:	LIPPINCOTT WILLIAMS & WILKINS
Place of Publication:	PHILADELPHIA
ISSN:	1524-4563
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language TYROSINE KINASE 1; CRYSTAL-STRUCTURE; ANGSTROM RESOLUTION; PREGNANT-WOMEN; IN-VIVO; HYPERTENSION; MODEL; GLYCOSYLATION; REMOVAL; COMPLEX Multiple languages Peripheral Vascular Disease Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/31767