Extracellular fragment of brain-specific angiogenesis inhibitor 1 suppresses endothelial cell proliferation by blocking αvβ5 integrin

Brain-specific angiogenesis inhibitor I (BAII) is a transmembrane protein with anti-angiogenic activity. The mechanisms underlying BAII activity are unknown. In this study, we found that overexpression of BAII increased cell death in human umbilical vein endothelial cells (HUVECs) and, to a lesser degree, in SHSY5Y and U343 cells. Conditioned medium from BAII-transfected U343 cells inhibited proliferation of HUVECs, and this effect was neutralized by addition of anti-BAII serum. The conditioned medium contained four cleavage products of the BAII extracellular domain. BAII's middle extracellular region containing five thrombospondin type I repeats (BAII-TSR) was sufficient for BAII's antiproliferative effect on HUVECs. BAII's action on HUVECs was blocked by anti-alpha(v) integrin, but not by anti-CD36 antibody treatment. Introduction Of alpha(v)beta(5) integrin into HEK293 cells rendered them susceptible to cell death by BAII, and BAII-TSR bound with alpha(v)beta(5) integrin, but not to alpha(4)beta(3) integrin in brain tissue. Fluorescent BAII-TSR colocalized with alpha(v)beta(5) integrin in HUVECs. Together, our results indicate that BAII has antiproliferative action on surrounding endothelial cells by blocking alpha(v)beta(5) integrin, and its active region is BAII-TSR. BAII-TSR could be valuable for regulating brain angiogenesis. (C) 2003 Elsevier Inc. All rights reserved.