Home News About Us Contact Contributors Disclaimer Privacy Policy Help FAQ

Home
Search
Quick Search
Advanced
Fulltext
Browse
Collections
Persons
My eDoc
Session History
Login
Name:
Password:
Documentation
Help
Support Wiki
Direct access to
document ID:


          Institute: MPI für molekulare Biomedizin     Collection: Jahrbuch 2016 (publ. 2015, arch)     Display Documents



  history
ID: 717267.0, MPI für molekulare Biomedizin / Jahrbuch 2016 (publ. 2015, arch)
FOXC2 and fluid shear stress stabilize postnatal lymphatic vasculature
Authors:Sabine, A.; Bovay, E.; Demir, C. S.; Kimura, W.; Jaquet, M.; Agalarov, Y.; Zangger, N.; Scallan, J. P.; Graber, W.; Gulpinar, E.; Kwak, B. R.; Makinen, T.; Martinez-Corral, I.; Ortega, S.; Delorenzi, M.; Kiefer, F.; Davis, M. J.; Djonov, V.; Miura, N.; Petrova, T. V.
Date of Publication (YYYY-MM-DD):2015-10-01
Title of Journal:J Clin Invest
Volume:125
Issue / Number:10
Start Page:3861
End Page:3877
Review Status:Internal review
Audience:Not Specified
Abstract / Description:Biomechanical forces, such as fluid shear stress, govern multiple aspects of endothelial cell biology. In blood vessels, disturbed flow is associated with vascular diseases, such as atherosclerosis, and promotes endothelial cell proliferation and apoptosis. Here, we identified an important role for disturbed flow in lymphatic vessels, in which it cooperates with the transcription factor FOXC2 to ensure lifelong stability of the lymphatic vasculature. In cultured lymphatic endothelial cells, FOXC2 inactivation conferred abnormal shear stress sensing, promoting junction disassembly and entry into the cell cycle. Loss of FOXC2-dependent quiescence was mediated by the Hippo pathway transcriptional coactivator TAZ and, ultimately, led to cell death. In murine models, inducible deletion of Foxc2 within the lymphatic vasculature led to cell-cell junction defects, regression of valves, and focal vascular lumen collapse, which triggered generalized lymphatic vascular dysfunction and lethality. Together, our work describes a fundamental mechanism by which FOXC2 and oscillatory shear stress maintain lymphatic endothelial cell quiescence through intercellular junction and cytoskeleton stabilization and provides an essential link between biomechanical forces and endothelial cell identity that is necessary for postnatal vessel homeostasis. As FOXC2 is mutated in lymphedema-distichiasis syndrome, our data also underscore the role of impaired mechanotransduction in the pathology of this hereditary human disease.
Free Keywords:Adaptor Proteins, Signal Transducing/physiology; Animals; Apoptosis; Cell Cycle; Cell Division; Cells, Cultured; Cytoskeleton/ultrastructure; Endothelial Cells/*cytology/pathology; Forkhead Transcription Factors/antagonists & inhibitors/deficiency/*physiology; Humans; Intercellular Junctions/ultrastructure; Lymphatic System/*growth & development; Lymphatic Vessels/*cytology/pathology; Mice; Mice, Inbred C57BL; Mice, Knockout; Phosphoproteins/physiology; RNA Interference; RNA, Small Interfering/pharmacology; *Rheology; Stress Fibers/ultrastructure; Stress, Mechanical; Transcription Factors/physiology; Transcription, Genetic; Transfection
External Publication Status:published
Document Type:Article
Communicated by:Keuker
Affiliations:MPI für molekulare Biomedizin
Identifiers:ISSN:1558-8238 (Electronic) 0021-9738 (Linking) %R 10.1... [ID No:1]
URL:http://www.ncbi.nlm.nih.gov/pubmed/26389677 [ID No:2]
The scope and number of records on eDoc is subject to the collection policies defined by each institute - see "info" button in the collection browse view.