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Originally published online as doi:10.2353/ajpath.2009.080625 on February 5, 2009

Published online before print February 5, 2009
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(American Journal of Pathology. 2009;174:1084-1096.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080625

Chloride Intracellular Channel Protein-4 Functions in Angiogenesis by Supporting Acidification of Vacuoles Along the Intracellular Tubulogenic Pathway

Barbara Ulmasov*, Jonathan Bruno{dagger}{ddagger}, Nicarter Gordon{dagger}{ddagger}, M. Elizabeth Hartnett§ and John C. Edwards{dagger}

From the Department of Medicine,* St. Louis University, St. Louis, Missouri; and the University of North Carolina Kidney Center,{dagger} and the Departments of Medicine,{ddagger} and Ophthalmology,§ University of North Carolina, Chapel Hill, North Carolina

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.




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