Reduction of circulating soluble Flt-1 alleviates preeclampsia-like symptoms in a mouse model

Abstract

Preeclampsia (PE) is characterized by widespread endothelial damage with hypertension, proteinuria, glomeruloendotheliosis and elevated soluble Flt-1 (sFlt-1), a natural occurring antagonist of vascular endothelial growth factor (VEGF). Cancer patients receiving anti-VEGF therapy exhibit similar symptoms. We suggested that a decrease in circulating sFlt-1 would alleviate the symptoms associated with PE. Adenoviral (Adv) overexpression of sFlt-1 induced proteinuria, caused glomerular damage and increase in blood pressure in female Balb/c mice. Circulating level of sFlt-1 above 50 ng/ml plasma induced severe vascular damage and glomerular endotheliosis. Albumin concentration in urine was elevated up to 30-fold, compared to control AdvGFP-treated animals. The threshold of kidney damage was in the range of 20-30 ng/ml sFlt-1 in plasma (8-15 ng/ml in urine). Co-administration of AdvsFlt-1 with AdvVEGF to neutralize circulating sFlt-1 resulted in more than a 70% reduction in free sFlt-1 in plasma, more than 80% reduction in urine and rescued the damaging effect of sFlt-1 on the kidneys. This demonstrates that below a critical threshold sFlt-1 fails to elicit damage to the fenestrated endothelium and that co-expression of VEGF is able to rescue effects mediated by sFlt-1 overexpression.

Publication DOI: https://doi.org/10.1111/j.1582-4934.2009.00820.x
Divisions: College of Health & Life Sciences > School of Biosciences
College of Health & Life Sciences > School of Biosciences > Cellular and Molecular Biomedicine
College of Health & Life Sciences > Aston Medical School
College of Health & Life Sciences
Additional Information: This is an Open Access article under the terms of the Creative Commons Attribution Non Commercial License which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
Uncontrolled Keywords: preeclampsia,vascular endothelial growth factor,fms-like tyrosine kinase receptor,vascular disease,Cell Biology,Molecular Medicine
Publication ISSN: 1582-4934
Last Modified: 29 Feb 2024 08:11
Date Deposited: 15 Feb 2013 09:48
Full Text Link: http://onlineli ... 0820.x/abstract
Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2010-06
Authors: Bergmann, Astrid
Ahmad, Shakil (ORCID Profile 0000-0002-9294-0475)
Cudmore, Melissa J.
Gruber, Achim D.
Wittschen, Petra
Lindenmaier, Werner
Christofori, Gerhard
Gross, Volkmar
Ch. da Costa Gonzalves, Andrey
Gröne, Hermann-Josef
Ahmed, Asif (ORCID Profile 0000-0002-8755-8546)
Weich, Herbert A.

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