Reduction of circulating soluble Flt-1 alleviates preeclampsia-like symptoms in a mouse model.
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.
Bergmann
Astrid
A
Departments of Gene Regulation and Differentiation, Helmholtz Centre for Infection Research, Braunschweig, Germany.
Ahmad
Shakil
S
Cudmore
Melissa
M
Gruber
Achim D
AD
Wittschen
Petra
P
Lindenmaier
Werner
W
Christofori
Gerhard
G
Gross
Volkmar
V
Gonzalves
Andrey Ch da Costa
ACh
Gröne
Hermann-Josef
HJ
Ahmed
Asif
A
Weich
Herbert A
HA
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D051379:Mice; D011225:Pre-Eclampsia / Q000097:blood* / Q000503:physiopathology; D011247:Pregnancy; D011485:Protein Binding / Q000187:drug effects; D012995:Solubility / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage / Q000494:pharmacology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2