caa a22 4500 357908090 20201218030336.0 cr unu---uuuuu 160309e20151001xx s 000 0 eng (BORIS)oai:boris.unibe.ch:76430 610 ddc FOXC2 and fluid shear stress stabilize postnatal lymphatic vasculature [Elektronische Daten] [Amélie Sabine, Esther Bovay, Cansaran Saygili Demir, Wataru Kimura, Muriel Jaquet, Yan Agalarov, Nadine Zangger, Joshua P Scallan, Werner Adrian 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] publishedVersion openAccess eu-repo 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. Sabine Amélie joint author Bovay Esther joint author Demir Cansaran Saygili joint author Kimura Wataru joint author Jaquet Muriel joint author Agalarov Yan joint author Zangger Nadine joint author Scallan Joshua P. joint author Graber Werner Adrian joint author Gulpinar Elgin joint author Kwak Brenda R. joint author Mäkinen Taija joint author Martinez-Corral Inés joint author Ortega Sagrario joint author Delorenzi Mauro joint author Kiefer Friedemann joint author Davis Michael J. joint author Djonov Valentin joint author Miura Naoyuki joint author Petrova Tatiana V. joint author Journal of clinical investigation 125(10), pp. 3861-3877 Onlinezugriff via WWW text/html Sabine, Amélie; Bovay, Esther; Demir, Cansaran Saygili; Kimura, Wataru; Jaquet, Muriel; Agalarov, Yan; Zangger, Nadine; Scallan, Joshua P; Graber, Werner Adrian; Gulpinar, Elgin; Kwak, Brenda R; Mäkinen, Taija; Martinez-Corral, Inés; Ortega, Sagrario; Delorenzi, Mauro; Kiefer, Friedemann; Davis, Michael J; Djonov, Valentin; Miura, Naoyuki and Petrova, Tatiana V (2015). FOXC2 and fluid shear stress stabilize postnatal lymphatic vasculature. Journal of clinical investigation, 125(10), pp. 3861-3877. American Society for Clinical Investigation 10.1172/JCI80454 <http://dx.doi.org/10.1172/JCI80454> BORIS BK010053 XK010053 XK010000 1 info:eu-repo/semantics/article boris PeerReviewed boris peerstatus BORIS BORIS BORIS info:eu-repo/semantics/article openAccess BORIS 856 42 Onlinezugriff via WWW text/html Sabine, Amélie; Bovay, Esther; Demir, Cansaran Saygili; Kimura, Wataru; Jaquet, Muriel; Agalarov, Yan; Zangger, Nadine; Scallan, Joshua P; Graber, Werner Adrian; Gulpinar, Elgin; Kwak, Brenda R; Mäkinen, Taija; Martinez-Corral, Inés; Ortega, Sagrario; Delorenzi, Mauro; Kiefer, Friedemann; Davis, Michael J; Djonov, Valentin; Miura, Naoyuki and Petrova, Tatiana V (2015). FOXC2 and fluid shear stress stabilize postnatal lymphatic vasculature. Journal of clinical investigation, 125(10), pp. 3861-3877. American Society for Clinical Investigation 10.1172/JCI80454 <http://dx.doi.org/10.1172/JCI80454> BORIS 700 1- Sabine Amélie joint author BORIS 700 1- Bovay Esther joint author BORIS 700 1- Demir Cansaran Saygili joint author BORIS 700 1- Kimura Wataru joint author BORIS 700 1- Jaquet Muriel joint author BORIS 700 1- Agalarov Yan joint author BORIS 700 1- Zangger Nadine joint author BORIS 700 1- Scallan Joshua P. joint author BORIS 700 1- Graber Werner Adrian joint author BORIS 700 1- Gulpinar Elgin joint author BORIS 700 1- Kwak Brenda R. joint author BORIS 700 1- Mäkinen Taija joint author BORIS 700 1- Martinez-Corral Inés joint author BORIS 700 1- Ortega Sagrario joint author BORIS 700 1- Delorenzi Mauro joint author BORIS 700 1- Kiefer Friedemann joint author BORIS 700 1- Davis Michael J. joint author BORIS 700 1- Djonov Valentin joint author BORIS 700 1- Miura Naoyuki joint author BORIS 700 1- Petrova Tatiana V. joint author BORIS 773 0- Journal of clinical investigation 125(10), pp. 3861-3877