VASP regulates leukocyte infiltration, polarization, and vascular repair after ischemia

J Cell Biol. 2018 Apr 2;217(4):1503-1519. doi: 10.1083/jcb.201702048. Epub 2018 Mar 5.

Abstract

In ischemic vascular diseases, leukocyte recruitment and polarization are crucial for revascularization and tissue repair. We investigated the role of vasodilator-stimulated phosphoprotein (VASP) in vascular repair. After hindlimb ischemia induction, blood flow recovery, angiogenesis, arteriogenesis, and leukocyte infiltration into ischemic muscles in VASP-/- mice were accelerated. VASP deficiency also elevated the polarization of the macrophages through increased signal transducer and activator of transcription (STAT) signaling, which augmented the release of chemokines, cytokines, and growth factors to promote leukocyte recruitment and vascular repair. Importantly, VASP deletion in bone marrow-derived cells was sufficient to mimic the increased blood flow recovery of global VASP-/- mice. In chemotaxis experiments, VASP-/- neutrophils/monocytes were significantly more responsive to M1-related chemokines than wild-type controls. Mechanistically, VASP formed complexes with the chemokine receptor CCR2 and β-arrestin-2, and CCR2 receptor internalization was significantly reduced in VASP-/- leukocytes. Our data indicate that VASP is a major regulator of leukocyte recruitment and polarization in postischemic revascularization and support a novel role of VASP in chemokine receptor trafficking.

Publication types

  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Actin Cytoskeleton / metabolism
  • Animals
  • Cell Adhesion Molecules / deficiency
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism*
  • Chemokines / metabolism
  • Chemotaxis, Leukocyte*
  • Disease Models, Animal
  • Hindlimb
  • Ischemia / genetics
  • Ischemia / metabolism*
  • Ischemia / pathology
  • Ischemia / physiopathology
  • Leukocytes / metabolism*
  • Macrophages / metabolism
  • Mice, Knockout
  • Microfilament Proteins / deficiency
  • Microfilament Proteins / genetics
  • Microfilament Proteins / metabolism*
  • Muscle, Skeletal / blood supply*
  • Neovascularization, Physiologic*
  • Neuropeptides / metabolism
  • Peritonitis / genetics
  • Peritonitis / metabolism*
  • Peritonitis / pathology
  • Peritonitis / physiopathology
  • Phenotype
  • Phosphoproteins / deficiency
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Protein Transport
  • Receptors, CCR2 / metabolism
  • STAT Transcription Factors / metabolism
  • Signal Transduction
  • Time Factors
  • beta-Arrestin 2 / metabolism
  • rac1 GTP-Binding Protein / metabolism

Substances

  • Arrb2 protein, mouse
  • Ccr2 protein, mouse
  • Cell Adhesion Molecules
  • Chemokines
  • Microfilament Proteins
  • Neuropeptides
  • Phosphoproteins
  • Rac1 protein, mouse
  • Receptors, CCR2
  • STAT Transcription Factors
  • beta-Arrestin 2
  • vasodilator-stimulated phosphoprotein
  • rac1 GTP-Binding Protein