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(Circulation Research. 2006;99:1207.)
© 2006 American Heart Association, Inc.

Molecular Medicine

Extracellular Matrix–Bound Angiopoietin-Like 4 Inhibits Endothelial Cell Adhesion, Migration, and Sprouting and Alters Actin Cytoskeleton

Aurélie Cazes, Ariane Galaup, Clémence Chomel, Marine Bignon, Nicolas Bréchot, Sébastien Le Jan, Holger Weber, Pierre Corvol, Laurent Muller, Stéphane Germain, Catherine Monnot

From INSERM U36, College de France (A.C., A.G., C.C., M.B., N.B., S.L.J., P.C., L.M., S.G., C.M.), 75005 Paris, France; Department of Vascular Biology and Angiogenesis Research (H.W.), Tumor Biology Center, Freiburg, Germany; and Service d’Hematologie Biologique A (S.G.), Hopital Europeen Georges Pompidou, Paris, France.

Correspondence to Catherine Monnot, INSERM U36, College de France, 75005 Paris, France. E-mail catherine.monnot{at}college-de-france.fr

Angiopoietin-like 4 (ANGPTL4) is a secreted protein that belongs to the angiopoietin family and is involved in angiogenesis and metabolism regulation. We previously reported the induction of angptl4 by hypoxia in endothelial cells and in human ischemic tissues from peripheral artery disease. We here observed in a mouse model of hindlimb ischemia that the mRNA upregulation in the vessels correlates with the accumulation of the full-length protein in ischemic tissues. We then investigated its functions in endothelial cells. In response to hypoxia, endogenous ANGPTL4 accumulates in the subendothelial extracellular matrix (ECM). Although the secreted protein undergoes proteolysis leading to truncated fragments present in the medium, only full-length ANGPTL4 interacts with the ECM. Competition and direct binding assays indicate that the strong interaction of ANGPTL4 with the ECM is heparin/heparan sulfate proteoglycan dependent. The balance between matrix-associated and soluble forms of ANGPTL4 points to the role of the ECM in the regulation of its bioavailability. The angiogenic function of the ECM-bound full-length protein was investigated using either the form associated with the conditioned ECM from ANGPTL4-transfected HEK293 cells or the purified immobilized protein. We show that matrix-associated and immobilized ANGPTL4 limit the formation of actin stress fibers and focal contacts in the adhering endothelial cells and inhibit their adhesion. Immobilized ANGPTL4 also decreases motility of endothelial cells and inhibits the sprouting and tube formation. Altogether, these findings show that hypoxic endothelial cells accumulate ANGPTL4 in the ECM, which in turn negatively regulates their angiogenic capacities through an autocrine pathway.

Key Words: extracellular matrix • endothelial cells • angiogenesis • hypoxia

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