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Intravital Microscopy of Monocyte Homing and Tumor-Related Angiogenesis in a Murine Model of Peripheral Arterial Disease
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Angiostatin inhibits monocyte/macrophage migration via disruption of actin cytoskeleton

Sabrina R Perri1, Borhane Annabi, Jacques Galipeau

  • 1Division of Experimental Medicine, Lady Davis Institute for Medical Research, McGill University, Montreal, Quebec, Canada H3T 1E2.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|July 12, 2007
PubMed

Insights

Human plasminogen angiostatin (hK1-3) protein effectively blocks macrophage migration and alters actin structure, offering potential therapeutic benefits for conditions like cancer and atherosclerosis.

Area of Science:

  • Immunology
  • Cancer Biology
  • Biochemistry

Background:

  • Tumor-associated macrophages (TAM) promote tumor growth and metastasis.
  • Strategies to inhibit TAM recruitment are under investigation.
  • Angiostatin has shown potential in reducing macrophage infiltration.

Purpose of the Study:

  • To investigate human plasminogen angiostatin (hK1-3) as a macrophage modulatory agent.
  • To explore the effects of hK1-3 on macrophage migration and cellular behavior.
  • To assess the therapeutic potential of hK1-3 in pathological conditions.

Main Methods:

  • In vitro migration assays using murine peritoneal macrophages and human monocytes.
  • Cell viability assessment using FLICA/PI flow cytometry.
  • Confocal microscopy of phalloidin-stained cells to analyze actin cytoskeleton.
  • Measurement of matrix metalloproteinase-9 (MMP-9) secretion and activity.
  • Analysis of extracellular signal-regulated kinase (ERK1/2) phosphorylation.

Main Results:

  • hK1-3 significantly decreased macrophage and monocyte migration (91% and 85% respectively).
  • Cell viability remained unaffected by hK1-3 treatment.
  • hK1-3 disrupted actin filopodia/lamellipodia in monocytes and induced podosome accumulation in macrophages.
  • MMP-9 secretion and gelatinolytic activity increased 3.5- to 5.5-fold.
  • hK1-3 induced ERK1/2 phosphorylation in human monocytes.

Conclusions:

  • hK1-3 effectively immobilizes macrophages, impacting their migration and cytoskeletal organization.
  • The observed increase in MMP-9 may be a compensatory response to hK1-3's static effect.
  • hK1-3-mediated macrophage immobilization presents a potential therapeutic strategy for hypoxia-associated diseases like cancer and atherosclerosis.

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