Flow-Dependent Endothelial YAP Regulation Contributes to Vessel Maintenance

Dev Cell. 2017 Mar 27;40(6):523-536.e6. doi: 10.1016/j.devcel.2017.02.019.

Abstract

Endothelial cells (ECs) line the inside of blood vessels and respond to mechanical cues generated by blood flow. Mechanical stimuli regulate the localization of YAP by reorganizing the actin cytoskeleton. Here we demonstrate blood-flow-mediated regulation of endothelial YAP in vivo. We indirectly monitored transcriptional activity of Yap1 (zebrafish YAP) and its spatiotemporal localization in living zebrafish and found that Yap1 entered the nucleus and promoted transcription in response to blood flow. In cultured human ECs, laminar shear stress induced nuclear import of YAP and its transcriptional activity in a manner independent of Hippo signaling. We uncovered a molecular mechanism by which flow induced the nuclear translocation of YAP through the regulation of filamentous actin and angiomotin. Yap1 mutant zebrafish showed a defect in vascular stability, indicating an essential role for Yap1 in blood vessels. Our data imply that endothelial Yap1 functions in response to flow to maintain blood vessels.

Keywords: Hippo pathway; fluid shear stress; mechanotransduction; vascular remodeling.

MeSH terms

  • Actins / metabolism
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Blood Vessels / metabolism*
  • Cell Nucleus / metabolism
  • Endothelial Cells / metabolism*
  • Hemorheology*
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Perfusion
  • Phosphoproteins / metabolism*
  • Protein Transport
  • Protein-Serine-Threonine Kinases / metabolism
  • Shear Strength
  • Signal Transduction / genetics
  • Stress, Mechanical
  • Trans-Activators / metabolism*
  • Transcription Factors
  • Transcription, Genetic
  • Transcriptional Activation / genetics
  • Zebrafish / embryology
  • Zebrafish / genetics
  • Zebrafish Proteins / metabolism*

Substances

  • Actins
  • Adaptor Proteins, Signal Transducing
  • Intercellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Phosphoproteins
  • Trans-Activators
  • Transcription Factors
  • YAP1 (Yes-associated) protein, human
  • Yes-associated protein (yap), zebrafish
  • Zebrafish Proteins
  • amot protein, zebrafish
  • Protein-Serine-Threonine Kinases
  • stk3 protein, zebrafish