Year: 2015
Type: article
Abstract: 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.
DOI: 10.1172/jci80454
Authors: Amélie Sabine, Esther Bovay, Cansaran Saygili Demir, Wataru Kimura, Muriel Jaquet, Yan Agalarov, Nadine Zangger, Joshua P. Scallan, Werner Graber, Elgin Gulpinar, Brenda R. Kwak, Taija Mäkinen, Inés Martinez-Corral, Sagrario Ortega, Mauro Delorenzi, Friedemann Kiefer, Michael J. Davis, Valentin Djonov, Naoyuki Miura, Tatiana V. Petrova
Institutions: Centre Hospitalier Universitaire Vaudois, University of Lausanne, Hamamatsu University School of Medicine, SIB Swiss Institute of Bioinformatics, University of Missouri, University of Bern, Harvard University, University of Geneva, Uppsala University, Spanish National Cancer Research Centre, Max Planck Institute for Molecular Biomedicine, Hamamatsu University, École Polytechnique Fédérale de Lausanne
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Awards: Cell-cell communication and mechano-transduction in lymphatic vascular morphogenesis and disease, Mechanisms of lymphatic valve and pump dysfunction in lymphedema, G3207356259, G393177772, Vascular Endothelial interactionS and SpEciaLization, Lymphatic pacemaking and pumping in lymphedema: function, dysfunction, and rescue, G5702163051, Transcription factors FOXC2 and PROX1 in lymphatic vascular development and cancer
OpenAlex ID: W2115152359