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Chloride intracellular channel protein-4 functions in angiogenesis by supporting acidification of vacuoles along the intracellular tubulogenic pathway.

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.

Pubmed ID: 19197003


  • Ulmasov B
  • Bruno J
  • Gordon N
  • Hartnett ME
  • Edwards JC


The American journal of pathology

Publication Data

March 23, 2009

Associated Grants

  • Agency: NIDDK NIH HHS, Id: R01 DK060551
  • Agency: NEI NIH HHS, Id: R01 EY015130

Mesh Terms

  • Animals
  • Cell Division
  • Chloride Channels
  • Endothelium, Vascular
  • Gene Amplification
  • Genome
  • Hydrogen-Ion Concentration
  • Mice
  • Mice, Knockout
  • Mitochondrial Proteins
  • Neovascularization, Pathologic
  • Neovascularization, Physiologic
  • Retina
  • Vacuoles