Mechanically activated ion channel PIEZO1 is required for lymphatic valve formation.

Autor:	Nonomura K; Howard Hughes Medical Institute, The Scripps Research Institute, La Jolla, CA 92037; nonomura@nibb.ac.jp ardem@scripps.edu.; Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037.; Division of Embryology, National Institute for Basic Biology, Okazaki, 444-8787, Japan.; Department of Basic Biology, School of Life Science, Okazaki, 444-8787, Japan., Lukacs V; Howard Hughes Medical Institute, The Scripps Research Institute, La Jolla, CA 92037.; Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037., Sweet DT; Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104., Goddard LM; Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104., Kanie A; Division of Embryology, National Institute for Basic Biology, Okazaki, 444-8787, Japan., Whitwam T; Howard Hughes Medical Institute, The Scripps Research Institute, La Jolla, CA 92037.; Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037., Ranade SS; Howard Hughes Medical Institute, The Scripps Research Institute, La Jolla, CA 92037.; Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037., Fujimori T; Division of Embryology, National Institute for Basic Biology, Okazaki, 444-8787, Japan.; Department of Basic Biology, School of Life Science, Okazaki, 444-8787, Japan., Kahn ML; Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104., Patapoutian A; Howard Hughes Medical Institute, The Scripps Research Institute, La Jolla, CA 92037; nonomura@nibb.ac.jp ardem@scripps.edu.; Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2018 Dec 11; Vol. 115 (50), pp. 12817-12822. Date of Electronic Publication: 2018 Nov 27.
DOI:	10.1073/pnas.1817070115
Abstrakt:	PIEZO1 is a cation channel that is activated by mechanical forces such as fluid shear stress or membrane stretch. PIEZO1 loss-of-function mutations in patients are associated with congenital lymphedema with pleural effusion. However, the mechanistic link between PIEZO1 function and the development or function of the lymphatic system is currently unknown. Here, we analyzed two mouse lines lacking PIEZO1 in endothelial cells (via Tie2Cre or Lyve1Cre ) and found that they exhibited pleural effusion and died postnatally. Strikingly, the number of lymphatic valves was dramatically reduced in these mice. Lymphatic valves are essential for ensuring proper circulation of lymph. Mechanical forces have been implicated in the development of lymphatic vasculature and valve formation, but the identity of mechanosensors involved is unknown. Expression of FOXC2 and NFATc1, transcription factors known to be required for lymphatic valve development, appeared normal in Tie2Cre;Piezo1 cKO mice. However, the process of protrusion in the valve leaflets, which is associated with collective cell migration, actin polymerization, and remodeling of cell-cell junctions, was impaired in Tie2Cre;Piezo1 cKO mice. Consistent with these genetic findings, activation of PIEZO1 by Yoda1 in cultured lymphatic endothelial cells induced active remodeling of actomyosin and VE-cadherin + cell-cell adhesion sites. Our analysis provides evidence that mechanically activated ion channel PIEZO1 is a key regulator of lymphatic valve formation. Competing Interests: The authors declare no conflict of interest. (Copyright © 2018 the Author(s). Published by PNAS.)
Databáze:	MEDLINE
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