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Impairment of angiogenesis and cell migration by targeted aquaporin-1 gene disruption

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.

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Figure 1: Reduced tumour growth in AQP1-null mice.
Figure 2: Angiogenesis in Matrigel and characterization of cultured endothelial cells.
Figure 3: Impaired migration of endothelial cells lacking AQP1.
Figure 4: Increased motility after transfection with aquaporin.

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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).

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Correspondence to A. S. Verkman.

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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)

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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

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  • DOI: https://doi.org/10.1038/nature03460

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