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

Astrid Bergmann, Shakil Ahmad, Melissa J. Cudmore, Achim D. Gruber, Petra Wittschen, Werner Lindenmaier, Gerhard Christofori, Volkmar Gross, Andrey Ch. da Costa Gonzalves, Hermann-Josef Gröne, Asif Ahmed, Herbert A. Weich

Research output: Contribution to journalArticle

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.
LanguageEnglish
Pages1857-1867
Number of pages11
JournalJournal of Cellular and Molecular Medicine
Volume14
Issue number6b
DOIs
Publication statusPublished - Jun 2010

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Pre-Eclampsia
Vascular Endothelial Growth Factor A
Urine
Proteinuria
Kidney
Endothelium
Blood Vessels
Albumins
Blood Pressure
Hypertension
Neoplasms
Therapeutics

Bibliographical note

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.

Keywords

  • preeclampsia
  • vascular endothelial growth factor
  • fms-like tyrosine kinase receptor
  • vascular disease

Cite this

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 ; Weich, Herbert A. / Reduction of circulating soluble Flt-1 alleviates preeclampsia-like symptoms in a mouse model. In: Journal of Cellular and Molecular Medicine. 2010 ; Vol. 14, No. 6b. pp. 1857-1867.
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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.",
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Bergmann, A, Ahmad, S, Cudmore, MJ, Gruber, AD, Wittschen, P, Lindenmaier, W, Christofori, G, Gross, V, Ch. da Costa Gonzalves, A, Gröne, H-J, Ahmed, A & Weich, HA 2010, 'Reduction of circulating soluble Flt-1 alleviates preeclampsia-like symptoms in a mouse model' Journal of Cellular and Molecular Medicine, vol. 14, no. 6b, pp. 1857-1867. https://doi.org/10.1111/j.1582-4934.2009.00820.x

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; Weich, Herbert A.

In: Journal of Cellular and Molecular Medicine, Vol. 14, No. 6b, 06.2010, p. 1857-1867.

Research output: Contribution to journalArticle

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T1 - Reduction of circulating soluble Flt-1 alleviates preeclampsia-like symptoms in a mouse model

AU - Bergmann, Astrid

AU - Ahmad, Shakil

AU - Cudmore, Melissa J.

AU - Gruber, Achim D.

AU - Wittschen, Petra

AU - Lindenmaier, Werner

AU - Christofori, Gerhard

AU - Gross, Volkmar

AU - Ch. da Costa Gonzalves, Andrey

AU - Gröne, Hermann-Josef

AU - Ahmed, Asif

AU - Weich, Herbert A.

N1 - 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.

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N2 - 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.

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