title: Release of cellular tension signals self-restorative ventral lamellipodia to heal barrier micro-wounds.
abstract: 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.
authors: Department of Medicine, Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors: Roberta
authors: R
authors: Martinelli
authors: Masataka
authors: M
authors: Kamei
authors: Peter T
authors: PT
authors: Sage
authors: Ramiro
authors: R
authors: Massol
authors: Laya
authors: L
authors: Varghese
authors: Tracey
authors: T
authors: Sciuto
authors: Mourad
authors: M
authors: Toporsian
authors: Ann M
authors: AM
authors: Dvorak
authors: Tomas
authors: T
authors: Kirchhausen
authors: Timothy A
authors: TA
authors: Springer
authors: Christopher V
authors: CV
authors: Carman
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D051376:Actin-Related Protein 2-3 Complex / Q000378:metabolism; D001696:Biomechanical Phenomena; D002448:Cell Adhesion; D002478:Cells, Cultured; D018920:Coculture Techniques; D051356:Cortactin / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000502:physiology*; D006801:Humans; D008214:Lymphocytes / Q000502:physiology; D008856:Microscopy, Fluorescence; D019255:NADPH Oxidases / Q000378:metabolism; D011554:Pseudopodia / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013312:Stress, Physiological; D059008:Time-Lapse Imaging; D057705:Transendothelial and Transepithelial Migration; D014945:Wound Healing; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D051376:Actin-Related Protein 2-3 Complex; C495868:CTTN protein, human; D051356:Cortactin; C107953:RAC1 protein, human; D017382:Reactive Oxygen Species; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D020830:rac1 GTP-Binding Protein
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