Release of cellular tension signals self-restorative ventral lamellipodia to heal barrier micro-wounds

J Cell Biol. 2013 Apr 29;201(3):449-65. doi: 10.1083/jcb.201209077.


Basic mechanisms by which cellular barriers sense and respond to integrity disruptions remain poorly understood. Despite its tenuous structure and constitutive exposure to disruptive strains, the vascular endothelium exhibits robust barrier function. We show that in response to micrometer-scale disruptions induced by transmigrating leukocytes, endothelial cells generate unique ventral lamellipodia that propagate via integrins toward and across these "micro-wounds" to close them. This novel actin remodeling activity progressively healed multiple micro-wounds in succession and changed direction during this process. Mechanical probe-induced micro-wounding of both endothelia and epithelia suggests that ventral lamellipodia formed as a response to force imbalance and specifically loss of isometric tension. Ventral lamellipodia were enriched in the Rac1 effectors cortactin, IQGAP, and p47Phox and exhibited localized production of hydrogen peroxide. Together with Apr2/3, these were functionally required for effective micro-wound healing. We propose that barrier disruptions are detected as local release of isometric tension/force unloading, which is directly coupled to reactive oxygen species-dependent self-restorative actin remodeling dynamics.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Actin Cytoskeleton / metabolism
  • Actin-Related Protein 2-3 Complex / metabolism
  • Biomechanical Phenomena
  • Cell Adhesion
  • Cells, Cultured
  • Coculture Techniques
  • Cortactin / metabolism
  • Human Umbilical Vein Endothelial Cells / physiology*
  • Humans
  • Lymphocytes / physiology
  • Microscopy, Fluorescence
  • NADPH Oxidases / metabolism
  • Pseudopodia / physiology*
  • Reactive Oxygen Species / metabolism
  • Stress, Physiological
  • Time-Lapse Imaging
  • Transendothelial and Transepithelial Migration*
  • Wound Healing
  • rac1 GTP-Binding Protein / metabolism


  • Actin-Related Protein 2-3 Complex
  • CTTN protein, human
  • Cortactin
  • RAC1 protein, human
  • Reactive Oxygen Species
  • NADPH Oxidases
  • neutrophil cytosolic factor 1
  • rac1 GTP-Binding Protein