Impairment of angiogenesis and cell migration by targeted aquaporin-1 gene disruption.
Aquaporin-1 (AQP1) is a water channel protein expressed widely in vascular endothelia, where it increases cell membrane water permeability. 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.
Saadoun
Samira
S
Department of Medicine, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California 94143, USA.
Papadopoulos
Marios C
MC
Hara-Chikuma
Mariko
M
Verkman
A S
AS
D000818:Animals; D051398:Aquaporin 1; D051400:Aquaporin 3; D051401:Aquaporin 4; D020346:Aquaporins / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D002448:Cell Adhesion; D002465:Cell Movement; D016764:Cell Polarity; D049109:Cell Proliferation; D002478:Cells, Cultured; D003094:Collagen; D004338:Drug Combinations; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism* / Q000473:pathology; D017353:Gene Deletion; D007797:Laminin; D008546:Melanoma, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D011509:Proteoglycans; D011554:Pseudopodia / Q000378:metabolism; D014867:Water / Q000378:metabolism; D014945:Wound Healing
C496021:Aqp1 protein, mouse; C496028:Aqp3 protein, mouse; C496031:Aqp4 protein, mouse; D051401:Aquaporin 4; D020346:Aquaporins; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D014867:Water; C059485:matrigel; D051398:Aquaporin 1; D051400:Aquaporin 3; D003094:Collagen