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

Astrid Bergmann, Shakil Ahmad, Melissa 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

99 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1857-1867
Number of pages11
JournalJournal of Cellular and Molecular Medicine
Volume14
Issue number6 B
DOIs
StatePublished - Jun 1 2010

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

Keywords

  • Fms-like tyrosine kinase receptor
  • Preeclampsia
  • Vascular disease
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Molecular Medicine
  • Cell Biology

Cite this

Bergmann, A., Ahmad, S., Cudmore, M., Gruber, A. D., Wittschen, P., Lindenmaier, W., ... Weich, H. A. (2010). Reduction of circulating soluble Flt-1 alleviates preeclampsia-like symptoms in a mouse model. Journal of Cellular and Molecular Medicine, 14(6 B), 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; Gruber, Achim D.; Wittschen, Petra; Lindenmaier, Werner; Christofori, Gerhard; Gross, Volkmar; Gonzalves, Andrey Ch da Costa; Gröne, Hermann Josef; Ahmed, Asif; Weich, Herbert A.

In: Journal of Cellular and Molecular Medicine, Vol. 14, No. 6 B, 01.06.2010, p. 1857-1867.

Research output: Contribution to journalArticle

Bergmann, A, Ahmad, S, Cudmore, M, Gruber, AD, Wittschen, P, Lindenmaier, W, Christofori, G, Gross, V, Gonzalves, ACDC, Gröne, HJ, 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. 6 B, pp. 1857-1867. https://doi.org/10.1111/j.1582-4934.2009.00820.x
Bergmann, Astrid ; Ahmad, Shakil ; Cudmore, Melissa ; Gruber, Achim D. ; Wittschen, Petra ; Lindenmaier, Werner ; Christofori, Gerhard ; Gross, Volkmar ; Gonzalves, Andrey Ch da Costa ; 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. 6 B. pp. 1857-1867.
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