Soluble Mediators Produced by Pro-Resolving Macrophages Inhibit Angiogenesis

Area of Science:

• Immunology
• Vascular Biology
• Tissue Repair

Background:

• Macrophages play diverse roles in inflammation and tissue repair.
• Alternatively activated macrophages promote angiogenesis via growth factors like VEGF.
• The role of macrophages in the anti-angiogenic phase of tissue repair is unclear.

Purpose of the Study:

• To investigate whether pro-resolving CD11blow macrophages (Mres) secrete mediators that inhibit angiogenesis.
• To determine the mechanisms by which Mre-derived mediators affect endothelial cells.

Main Methods:

• Assessed the effect of Mre-conditioned media (CM-Mres) on human umbilical vein endothelial cell (HUVEC) proliferation, survival, migration, and differentiation in vitro.
• Analyzed CM-Mres' impact on VEGFR2 activation and cyclin D1 expression.
• Evaluated CM-Mres' anti-angiogenic potential using ex vivo (rat aorta ring assay) and in vivo (chick chorioallantoic membrane assay) models.
• Identified endostatin as a key anti-angiogenic mediator produced by Mres.

Main Results:

• CM-Mres inhibited HUVEC proliferation, survival, and migration.
• CM-Mres reduced cyclin D1 expression and caspase 3/7 activation in HUVECs.
• VEGF-induced VEGFR2 activation was inhibited by CM-Mres.
• Both ex vivo and in vivo assays confirmed the anti-angiogenic effect of CM-Mres.
• Mres were found to produce endostatin, a known anti-angiogenic factor.

Conclusions:

• Pro-resolving Mres produce soluble mediators with potent anti-angiogenic properties.
• These mediators, including endostatin, inhibit endothelial cell proliferation, survival, and migration by targeting VEGFR2.
• Macrophages play a crucial role in the resolution of tissue repair by actively suppressing angiogenesis, thus restoring tissue homeostasis.