FOXC2 and fluid shear stress stabilize postnatal lymphatic vasculature

J Clin Invest. 2015 Oct 1;125(10):3861-77. doi: 10.1172/JCI80454. Epub 2015 Sep 21.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Adaptor Proteins, Signal Transducing / physiology
  • Animals
  • Apoptosis
  • Cell Cycle
  • Cell Division
  • Cells, Cultured
  • Cytoskeleton / ultrastructure
  • Endothelial Cells / cytology*
  • Endothelial Cells / pathology
  • Forkhead Transcription Factors / antagonists & inhibitors
  • Forkhead Transcription Factors / deficiency
  • Forkhead Transcription Factors / physiology*
  • Humans
  • Intercellular Junctions / ultrastructure
  • Lymphatic System / growth & development*
  • Lymphatic Vessels / cytology*
  • Lymphatic Vessels / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phosphoproteins / physiology
  • RNA Interference
  • RNA, Small Interfering / pharmacology
  • Rheology*
  • Stress Fibers / ultrastructure
  • Stress, Mechanical
  • Transcription Factors / physiology
  • Transcription, Genetic
  • Transfection

Substances

  • Adaptor Proteins, Signal Transducing
  • Forkhead Transcription Factors
  • Phosphoproteins
  • RNA, Small Interfering
  • TAZ protein, human
  • Transcription Factors
  • YAP1 (Yes-associated) protein, human
  • mesenchyme fork head 1 protein