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FOXC2 and fluid shear stress stabilize postnatal lymphatic vasculature

Sabine, Amélie
Bovay, Esther
Demir, Cansaran Saygili
Kimura, Wataru
Jaquet, Muriel
Agalarov, Yan
Scallan, Joshua P
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Published in Journal of Clinical Investigation. 2015, vol. 125, no. 10, p. 3861-3877
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.
PMID: 26389677
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Research group L'athérosclérose (665)
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SABINE, Amélie et al. FOXC2 and fluid shear stress stabilize postnatal lymphatic vasculature. In: Journal of Clinical Investigation, 2015, vol. 125, n° 10, p. 3861-3877. doi: 10.1172/JCI80454 https://archive-ouverte.unige.ch/unige:76937

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Deposited on : 2015-11-06

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