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PMID:19197003

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Citation

Ulmasov, B, Bruno, J, Gordon, N, Hartnett, ME and Edwards, JC (2009) Chloride intracellular channel protein-4 functions in angiogenesis by supporting acidification of vacuoles along the intracellular tubulogenic pathway. Am. J. Pathol. 174:1084-96

Abstract

Endothelial cells form capillary tubes through the process of intracellular tubulogenesis. Chloride intracellular channel (CLIC) family proteins have been previously implicated in intracellular tubulogenesis, but their specific role has not been defined. In this study, we show that disruption of the Clic4 gene in mice results in defective angiogenesis in vivo as reflected in a Matrigel plug angiogenesis assay. An angiogenesis defect is also apparent in the retina, both in the decreased spontaneous development of retinal vasculature of unstressed mice and in the dramatically decreased angiogenic response of retinal vessels to an oxygen toxicity challenge. We found that endothelial cells derived from Clic4(-/-) mice demonstrated impaired tubulogenesis in three-dimensional fibrin gels compared with cells derived from wild-type mice. Furthermore, we found that tubulogenesis of wild-type cells in culture was inhibited by both an inhibitor of CLICs and an inhibitor of the vacuolar proton ATPase. Finally, we showed that vacuoles along the endothelial tubulogenesis pathway are acidic in wild-type cells, and that vacuolar acidification is impaired in Clic4(-/-) cells while lysosomal acidification is intact. We conclude that CLIC4 plays a critical role in angiogenesis by supporting acidification of vacuoles along the cell-hollowing tubulogenic pathway.

Links

PubMed PMC2665767 Online version:10.2353/ajpath.2009.080625

Keywords

Animals; Cell Division; Chloride Channels/deficiency; Chloride Channels/genetics; Endothelium, Vascular/cytology; Gene Amplification; Genome; Hydrogen-Ion Concentration; Mice; Mice, Knockout; Mitochondrial Proteins/deficiency; Mitochondrial Proteins/genetics; Neovascularization, Pathologic/genetics; Neovascularization, Physiologic/genetics; Retina/cytology; Retina/pathology; Vacuoles/physiology

Significance

Annotations

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

MOUSE:CLIC4

acts_upstream_of_or_within

GO:0001886: endothelial cell morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3838012

P

Seeded From UniProt

complete

MOUSE:CLIC4

acts_upstream_of_or_within

GO:0001525: angiogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3838012

P

Seeded From UniProt

complete

MOUSE:CLIC4

acts_upstream_of_or_within

GO:0007035: vacuolar acidification

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3838012

P

Seeded From UniProt

complete

MOUSE:CLIC4

acts_upstream_of_or_within

GO:0009566: fertilization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:CLIC4

acts_upstream_of_or_within

GO:0061299: retina vasculature morphogenesis in camera-type eye

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3838012

P

Seeded From UniProt

complete

MOUSE:CLIC4

acts_upstream_of_or_within

GO:0048754: branching morphogenesis of an epithelial tube

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3838012

P

Seeded From UniProt

complete

MOUSE:CLIC4

acts_upstream_of_or_within

GO:0035264: multicellular organism growth

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3838012

P

Seeded From UniProt

complete


See also

References

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