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

Research output: Contribution to journalArticle

Authors

  • A Bergmann
  • AD Gruber
  • P Wittschen
  • W Lindenmaier
  • G Christofori
  • V Gross
  • AC da Costa Gonzalves
  • HJ Groene
  • HA Weich

Colleges, School and Institutes

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.

Details

Original languageEnglish
Pages (from-to)1857-1867
Number of pages11
JournalJournal of Cellular and Molecular Medicine
Volume14
Issue number6B
Publication statusPublished - 1 Jun 2010

Keywords

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