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

Bergmann, Astrid; Ahmad, Shakil; Cudmore, Melissa J.; Gruber, Achim D.; Wittschen, Petra; Lindenmaier, Werner; Christofori, Gerhard; Gross, Volkmar; Ch. da Costa Gonzalves, Andrey; Gröne, Hermann-Josef; Ahmed, Asif and Weich, Herbert A. Reduction of circulating soluble Flt-1 alleviates preeclampsia-like symptoms in a mouse model. Journal of Cellular and Molecular Medicine, 14 (6b), pp. 1857-1867.

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: Life & Health Sciences > Biosciences
Aston Medical School
Life & Health Sciences
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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

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