Establishment of a mouse model for the induction of preeclampsia by soluble VEGFR-1/flt-1 and its modulation by exogenous treatment with antibodies and receptor ligands

• Applicant: Dr. Herbert A. Weich
• Subject Area: Pathology
• Term: from 2006 to 2007
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 29241972

Our work hypothesis during the last 24 months was that VEGF-A together with PIGF must be very well regulated and that intratissual balance between sFlt-1 and VEGF/PIGF levels seems to play a crucial role for maintaining vascular homeostasis and that dysregulation of this balance is involved in several vascular diseases. This increasing levels of sFlt-1 secreted from placenta into the maternal blood are associated with decreasing circulating levels of free VEGF-A and PIGF and results in endothelial dysfunction in vivo. In the last period we have sucessfully established a mouse model for preeclampsia using adenoviral overexpression for sFlt-1 in Balb/c mice. This was achieved by intravenous injection of 2.5-5 x108 virus particles into the tail vein of 8-11 week old animals. After 8-10 days animals were sacrified and the glomeruli of the kidney were analyzed by histochemical analysis. Soluble flt-1 overexpression leads to a collapse of microvessels and tubes indicated by a strong reduction of microvessel lumen in a glomerulus. Injection of adenovirus also lead to a massive increase in liver volumen of virus treated animals, indicating that most of the injected virus particles were localized in the liver. So far parameter like blood pressure and proteinuria were not investigated in detail. In order to modulate the pathological effect in the kidney we have started to develop blocking antibodies by phage-display. Because this is a high risk part of the project, we were able to recrute blocking antibodies for flt-1 from a collaborating group. The sflt-1 effect induced for kidney dysfunction will now be analyzed in the last period in great detail. For this purpose we will also start a collaboration to measure induction of high blood pressure by telemetry and want to investigate our question, if blocking antibody to flt-1 can modulate the effect of preeclampsia experimentally induced in mice.

• DFG Programme: Research Grants