FOXC2 and fluid shear stress stabilize postnatal lymphatic vasculature

Article Article scientifique Article FOXC2 and fluid shear stress stabilize postnatal lymphatic vasculature eng 2015 author Sabine Amélie author Bovay Esther author Demir Cansaran Saygili author Kimura Wataru author Jaquet Muriel author Agalarov Yan author Zangger Nadine 519791 author Scallan Joshua P author Graber Werner author Gulpinar Elgin author Kwak Brenda 113350 author Mäkinen Taija author Martinez-Corral Inés author Ortega Sagrario author Delorenzi Mauro author Kiefer Friedemann author Davis Michael J author Djonov Valentin author Miura Naoyuki author Petrova Tatiana V 3861-3877 10.1172/JCI80454 26389677 0021-9738 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. Dewey 616 Dewey 616.07 137 Département de pathologie et immunologie 21F 56 Département de médecine 221 false 397 Connexines et pathologies cardiovasculaires 665 The Journal of clinical investigation 125 10 d65fe6d6-348e-4c9f-bc18-d3e92bc6631a Article (Published version) Restricted JCI80454.pdf 10934388 application/pdf restrictedAccess Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie Faculté de médecine / Section de médecine clinique / Département de médecine

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FOXC2 and fluid shear stress stabilize postnatal lymphatic vasculature	The Journal of clinical investigation	2015	453	1
Development and validation of a novel method for clustering protein sequences and detecting diagnostic motifs		2007	1,018	79

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Zangger, Nadine