Elevated soluble Flt1 inhibits endothelial repair in PR3-ANCA-associated vasculitis.
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis exhibits endothelial damage, but the capacity for vessel repair in this disorder is not well understood. Here, we observed a marked increase in serum levels of soluble Flt1 (sFlt1), a potent inhibitor of vascular endothelial growth factor, in patients with active ANCA-associated vasculitis compared with patients during remission and other controls. Serum levels of sFlt1 correlated with C5a, an anaphylatoxin released after complement activation. Serum from patients with acute ANCA-associated vasculitis disrupted blood flow in the chicken chorioallantoic membrane assay, suggesting an antiangiogenic effect. Preincubation with excess human vascular endothelial growth factor prevented this effect. Anti-proteinase-3 (PR3) mAb and serum containing PR3-ANCA from patients with active vasculitis both induced a significant and sustained release of sFlt1 from monocytes, whereas anti-myeloperoxidase (MPO) mAb or polyclonal antibodies did not. However, the serum containing polyclonal PR3-ANCA did not induce release of sFlt1 from cultured human umbilical vein endothelial cells. In summary, these data suggest that anti-PR3 antibodies, and to a much lesser extent anti-MPO antibodies, increase sFlt1 during acute ANCA-associated vasculitis, leading to an antiangiogenic state that hinders endothelial repair.
ITUN, U643, Department of Nephrology and Immunology, CHU de Nantes, 44000 Nantes, France.
Sandrine
S
Le Roux
Ruth J
RJ
Pepper
Alexandre
A
Dufay
Mélanie
M
Néel
Emmanuelle
E
Meffray
Noël
N
Lamandé
Marie
M
Rimbert
Régis
R
Josien
Mohamed
M
Hamidou
Maryvonne
M
Hourmant
H Terence
HT
Cook
Béatrice
B
Charreau
Etienne
E
Larger
Alan D
AD
Salama
Fadi
F
Fakhouri
D000818:Animals; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Q000097:blood* / Q000503:physiopathology; D016022:Case-Control Studies; D002642:Chick Embryo; D049033:Chorioallantoic Membrane; D015936:Complement C5a / Q000378:metabolism; D004730:Endothelium, Vascular / Q000503:physiopathology*; D006801:Humans; D009000:Monocytes / Q000378:metabolism; D053146:Myeloblastin / Q000276:immunology; D018919:Neovascularization, Physiologic; D020033:Protein Isoforms / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood* / Q000378:metabolism
D020033:Protein Isoforms; D015936:Complement C5a; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D053146:Myeloblastin