Open AccessElevated Soluble Flt1 Inhibits Endothelial Repair in PR3-ANCA–Associated Vasculitis
Author(s) -
Sandrine Roux,
Ruth J. Pepper,
Alexandre Dufay,
Mélanie Néel,
Emmanuelle Meffray,
Noël Lamandé,
Marie Rimbert,
Régis Josien,
M. Hamidou,
Maryvonne Hourmant,
H. Terence Cook,
Béatrice Charreau,
Étienne Larger,
Alan D. Salama,
Fádi Fakhouri
Publication year - 2012
Publication title -
journal of the american society of nephrology
Language(s) - Uncategorized
Resource type - Journals
SCImago Journal Rank - 4.451
H-Index - 279
eISSN - 1533-3450
pISSN - 1046-6673
DOI - 10.1681/asn.2010080858
Subject(s) - vasculitis , medicine , immunology , polyclonal antibodies , proteinase 3 , antibody , umbilical vein , microscopic polyangiitis , anti neutrophil cytoplasmic antibody , vascular endothelial growth factor , pathology , autoantibody , chemistry , biochemistry , disease , in vitro , vegf receptors
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.