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PMID:21835952

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Citation

Bignon, M, Pichol-Thievend, C, Hardouin, J, Malbouyres, M, Bréchot, N, Nasciutti, L, Barret, A, Teillon, J, Guillon, E, Etienne, E, Caron, M, Joubert-Caron, R, Monnot, C, Ruggiero, F, Muller, L and Germain, S (2011) Lysyl oxidase-like protein-2 regulates sprouting angiogenesis and type IV collagen assembly in the endothelial basement membrane. Blood 118:3979-89

Abstract

Sprouting angiogenesis is associated with extensive extracellular matrix (ECM) remodeling. The molecular mechanisms involved in building the vascular microenvironment and its impact on capillary formation remain elusive. We therefore performed a proteomic analysis of ECM from endothelial cells maintained in hypoxia, a major stimulator of angiogenesis. Here, we report the characterization of lysyl oxidase-like protein-2 (LOXL2) as a hypoxia-target expressed in neovessels and accumulated in the endothelial ECM. LOXL2 belongs to the lysyl oxidase family of secreted enzymes involved in ECM crosslinking. Knockdown experiments in Tg(fli1:egfp)y1 zebrafish embryos resulted in lack of intersegmental vessel circulation and demonstrated LOXL2 involvement in proper capillary formation. Further investigation in vitro by loss and gain of function experiments confirmed that LOXL2 was required for tubulogenesis in 3D fibrin gels and demonstrated that this enzyme was required for collagen IV assembly in the ECM. In addition, LOXL2 depletion down-regulated cell migration and proliferation. These data suggest a major role for LOXL2 in the organization of endothelial basal lamina and in the downstream mechanotransductive signaling. Altogether, our study provides the first evidence for the role of LOXL2 in regulating angiogenesis through collagen IV scaffolding.

Links

PubMed Online version:10.1182/blood-2010-10-313296

Keywords

Amino Acid Oxidoreductases/genetics; Amino Acid Oxidoreductases/metabolism; Animals; Basement Membrane/metabolism; Cell Hypoxia; Cell Line; Cell Movement; Collagen Type IV/metabolism; Endothelial Cells/cytology; Endothelial Cells/metabolism; Endothelium, Vascular/cytology; Extracellular Matrix/metabolism; Humans; Mice; Mice, Inbred C57BL; Neovascularization, Physiologic; Up-Regulation; Zebrafish/embryology; Zebrafish Proteins/genetics; Zebrafish Proteins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

RAT:LOXL2

located_in

GO:0005604: basement membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

DANRE:LOL2A

involved_in

GO:0002040: sprouting angiogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DANRE:LOL2A

involved_in

GO:0002040: sprouting angiogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-121101-2

P

Seeded From UniProt

complete

MOUSE:LOXL2

involved_in

GO:0001666: response to hypoxia

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:LOXL2

involved_in

GO:0030199: collagen fibril organization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:LOXL2

involved_in

GO:0002040: sprouting angiogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:LOXL2

involved_in

GO:0001935: endothelial cell proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:LOXL2

involved_in

GO:0043542: endothelial cell migration

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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