Abstract
Aquaporin-1 (AQP1) is a water channel protein expressed widely in vascular endothelia, where it increases cell membrane water permeability1,2,3. The role of AQP1 in endothelial cell function is unknown. Here we show remarkably impaired tumour growth in AQP1-null mice after subcutaneous or intracranial tumour cell implantation, with reduced tumour vascularity and extensive necrosis. A new mechanism for the impaired angiogenesis was established from cell culture studies. Although adhesion and proliferation were similar in primary cultures of aortic endothelia from wild-type and from AQP1-null mice, cell migration was greatly impaired in AQP1-deficient cells, with abnormal vessel formation in vitro. Stable transfection of non-endothelial cells with AQP1 or with a structurally different water-selective transporter (AQP4) accelerated cell migration and wound healing in vitro. Motile AQP1-expressing cells had prominent membrane ruffles at the leading edge with polarization of AQP1 protein to lamellipodia, where rapid water fluxes occur. Our findings support a fundamental role of water channels in cell migration, which is central to diverse biological phenomena including angiogenesis, wound healing, tumour spread and organ regeneration.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Nielsen, S., Smith, B. L., Christensen, E. I. & Agre, P. Distribution of the aquaporin CHIP in secretory and resorptive epithelia and capillary endothelia. Proc. Natl Acad. Sci. USA 90, 7275–7279 (1993)
Hasegawa, H., Lian, S. C., Finkbeiner, W. E. & Verkman, A. S. Extrarenal tissue distribution of CHIP28 water channels by in situ hybridization and antibody staining. Am. J. Physiol. 266, C893–C903 (1994)
Carter, E. P., Olveczky, B. P., Matthay, M. A. & Verkman, A. S. High microvascular endothelial water permeability in mouse lung measured by a pleural surface fluorescence method. Biophys. J. 74, 2121–2128 (1998)
Saadoun, S., Papadopoulos, M. C., Davies, D. C., Bell, B. A. & Krishna, S. Increased aquaporin 1 water channel expression in human brain tumours. Br. J. Cancer 87, 621–623 (2002)
Endo, M., Jain, R. K., Witwer, B. & Brown, D. Water channel (aquaporin 1) expression and distribution in mammary carcinomas and glioblastomas. Microvasc. Res. 58, 89–98 (1999)
Vacca, A. et al. Microvessel overexpression of aquaporin 1 parallels bone marrow angiogenesis in patients with active multiple myeloma. Br. J. Haematol. 113, 415–421 (2001)
Ribatti, D. et al. Aquaporin-1 expression in the chick embryo chorioallantoic membrane. Anat. Rec. 268, 85–89 (2002)
Moon, C. et al. Involvement of aquaporins in colorectal carcinogenesis. Oncogene 22, 6699–6703 (2003)
Egami, K. et al. Role of host angiotensin II type 1 receptor in tumor angiogenesis and growth. J. Clin. Invest. 112, 67–75 (2003)
Miao, W. M. et al. Thrombospondin-1 type 1 repeat recombinant proteins inhibit tumor growth through transforming growth factor-beta-dependent and -independent mechanisms. Cancer Res. 61, 7830–7839 (2001)
Ma, T. et al. Nephrogenic diabetes insipidus in mice lacking aquaporin-3 water channels. Proc. Natl Acad. Sci. USA 97, 4386–4391 (2000)
Yao, L. et al. Contribution of natural killer cells to inhibition of angiogenesis by interleukin-12. Blood 93, 1612–1621 (1999)
Solenov, E., Watanabe, H., Manley, G. T. & Verkman, A. S. Sevenfold-reduced osmotic water permeability in primary astrocyte cultures from AQP-4-deficient mice, measured by a fluorescence quenching method. Am. J. Physiol. Cell Physiol. 286, C426–C432 (2004)
Steinle, J. J. et al. Eph B4 receptor signaling mediates endothelial cell migration and proliferation via the phosphatidylinositol 3-kinase pathway. J. Biol. Chem. 277, 43830–43835 (2002)
Shi, G. P. et al. Deficiency of the cysteine protease cathepsin S impairs microvessel growth. Circ. Res. 92, 493–500 (2003)
Troyanovsky, B., Levchenko, T., Mansson, G., Matvijenko, O. & Holmgren, L. Angiomotin: an angiostatin binding protein that regulates endothelial cell migration and tube formation. J. Cell Biol. 152, 1247–1254 (2001)
Ishida, T. et al. Targeted disruption of endothelial cell-selective adhesion molecule inhibits angiogenic processes in vitro and in vivo. J. Biol. Chem. 278, 34598–34604 (2003)
Orr, A. W., Elzie, C. A., Kucik, D. F. & Murphy-Ullrich, J. E. Thrombospondin signaling through the calreticulin/LDL receptor-related protein co-complex stimulates random and directed cell migration. J. Cell Sci. 116, 2917–2927 (2003)
Lee, H., Goetzl, E. J. & An, S. Lysophosphatidic acid and sphingosine 1-phosphate stimulate endothelial cell wound healing. Am. J. Physiol. Cell Physiol. 278, C612–C618 (2000)
Schwab, A., Schuricht, B., Seeger, P., Reinhardt, J. & Dartsch, P. C. Migration of transformed renal epithelial cells is regulated by K+ channel modulation of actin cytoskeleton and cell volume. Pflugers Arch. 438, 330–337 (1999)
Schwab, A. Function and spatial distribution of ion channels and transporters in cell migration. Am. J. Physiol. Renal Physiol. 280, F739–F747 (2001)
Rosengren, S., Henson, P. M. & Worthen, G. S. Migration-associated volume changes in neutrophils facilitate the migratory process in vitro. Am. J. Physiol. 267, C1623–C1632 (1994)
Lauffenburger, D. A. & Horwitz, A. F. Cell migration: a physically integrated molecular process. Cell 84, 359–369 (1996)
Condeelis, J. Life at the leading edge: the formation of cell protrusions. Annu. Rev. Cell Biol. 9, 411–444 (1993)
Yang, B., Brown, D. & Verkman, A. S. The mercurial insensitive water channel (AQP-4) forms orthogonal arrays in stably transfected Chinese hamster ovary cells. J. Biol. Chem. 271, 4577–4580 (1996)
Ma, T. et al. Severely impaired urinary concentrating ability in transgenic mice lacking aquaporin-1 water channels. J. Biol. Chem. 273, 4296–4299 (1998)
Papadopoulos, M. C., Manley, G. T., Krishna, S. & Verkman, A. S. Aquaporin-4 facilitates reabsorption of excess fluid in vasogenic brain edema. FASEB J. 18, 1291–1293 (2004)
Kawamoto, A. et al. Intramyocardial transplantation of autologous endothelial progenitor cells for therapeutic neovascularization of myocardial ischemia. Circulation 107, 461–468 (2003)
Acknowledgements
This work was funded by grants from the National Institutes of Health (to A.S.V.) and by a Wellcome Trust Clinician Scientist Fellowship (to M.C.P., sponsored by S. Krishna).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare that they have no competing financial interests.
Supplementary information
Supplementary Figure S1
AQP1-CHO cells stained with Wheat Germ agglutinin as a plasma membrane marker, and immunostained for AQP1. (PDF 710 kb)
Supplementary Video S1
Migrating CHO cells, showing control cells (left) and AQP1-expressing cells (right). Four-hour recording, playback 720× faster. (AVI 4879 kb)
Supplementary Video S2
Migrating CHO cells, showing control cells (left) and AQP1-expressing cells (right). Two-minute recording, playback 10× faster. (AVI 4927 kb)
Rights and permissions
About this article
Cite this article
Saadoun, S., Papadopoulos, M., Hara-Chikuma, M. et al. Impairment of angiogenesis and cell migration by targeted aquaporin-1 gene disruption. Nature 434, 786–792 (2005). https://doi.org/10.1038/nature03460
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/nature03460
This article is cited by
-
The role of Aquaporins in tumorigenesis: implications for therapeutic development
Cell Communication and Signaling (2024)
-
Aquaporin 1 overexpression may enhance glioma tumorigenesis by interacting with the transcriptional regulation networks of Foxo4, Maz, and E2F families
Chinese Neurosurgical Journal (2023)
-
Aquaporin water channels: roles beyond renal water handling
Nature Reviews Nephrology (2023)
-
Aquaporin-mediated dysregulation of cell migration in disease states
Cellular and Molecular Life Sciences (2023)
-
Aquaporins Display a Diversity in their Substrates
The Journal of Membrane Biology (2023)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.