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    Reduction of Circulating Soluble Flt-1 Alleviates Preeclampsia-like Symptoms in a Mouse Model (2009)

    Art
    Zeitschriftenartikel / wissenschaftlicher Beitrag
    Autoren
    Bergmann, Astrid
    Ahmad, Shakil
    Cudmore, Melissa
    Gruber, Achim D.
    Wittschen, Petra
    Lindenmaier, Werner
    Christofori, Gerhard
    Gross, Volkmar
    Costa Gonzalves, Andrey Ch. da
    Gröne, Hermann-Josef
    Ahmed, Asif
    Weich, Herbert A.
    Quelle
    Journal of cellular and molecular medicine; 14(6) — S. 1857–1867
    ISSN: 1582-4934
    Sprache
    Englisch
    Verweise
    DOI: 10.1111/j.1582-4934.2009.00820.x
    Pubmed: 19538465
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    Gebäude 12
    14163 Berlin
    +49 30 838 62450

    Abstract / Zusammenfassung

    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.