title: FOXC2 and fluid shear stress stabilize postnatal lymphatic vasculature.
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.
authors.forename: Amélie
authors.initials: A
authors.lastname: Sabine
authors.forename: Esther
authors.initials: E
authors.lastname: Bovay
authors.forename: Cansaran Saygili
authors.initials: CS
authors.lastname: Demir
authors.forename: Wataru
authors.initials: W
authors.lastname: Kimura
authors.forename: Muriel
authors.initials: M
authors.lastname: Jaquet
authors.forename: Yan
authors.initials: Y
authors.lastname: Agalarov
authors.forename: Nadine
authors.initials: N
authors.lastname: Zangger
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Scallan
authors.forename: Werner
authors.initials: W
authors.lastname: Graber
authors.forename: Elgin
authors.initials: E
authors.lastname: Gulpinar
authors.forename: Brenda R
authors.initials: BR
authors.lastname: Kwak
authors.forename: Taija
authors.initials: T
authors.lastname: Mäkinen
authors.forename: Inés
authors.initials: I
authors.lastname: Martinez-Corral
authors.forename: Sagrario
authors.initials: S
authors.lastname: Ortega
authors.forename: Mauro
authors.initials: M
authors.lastname: Delorenzi
authors.forename: Friedemann
authors.initials: F
authors.lastname: Kiefer
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Davis
authors.forename: Valentin
authors.initials: V
authors.lastname: Djonov
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Miura
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Petrova
mesh_terms: D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D002455:Cell Division; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000648:ultrastructure; D042783:Endothelial Cells / Q000166:cytology* / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D006801:Humans; D007365:Intercellular Junctions / Q000648:ultrastructure; D008208:Lymphatic System / Q000254:growth & development*; D042601:Lymphatic Vessels / Q000166:cytology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000502:physiology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D012212:Rheology; D022502:Stress Fibers / Q000648:ultrastructure; D013314:Stress, Mechanical; D014157:Transcription Factors / Q000502:physiology; D014158:Transcription, Genetic; D014162:Transfection; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051858:Forkhead Transcription Factors; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C082078:mesenchyme fork head 1 protein; D000217:Acyltransferases; C108675:TAFAZZIN protein, human