Role of M2-like macrophage recruitment during angiogenic growth factor therapy.

Abstract

Therapeutic angiogenesis has yet to fulfill its promise for the clinical treatment of ischemic diseases. Given the impact of macrophages during pathophysiological angiogenesis, we asked whether macrophages may similarly modulate vascular responses to targeted angiogenic therapies. Mouse matrigel plug assay and rat myocardial infarction (MI) model were used to assess angiogenic therapy with either VEGF-A or FGF-2 with HGF (F+H) delivered locally via albumin-alginate microcapsules. The infiltration of classical M1-type and alternative M2-like macrophages was assessed. Clodronate was used to prevent macrophage recruitment, and the VEGFR2 blocking antibody, DC101, to prevent VEGF-A signaling. At 3 weeks after matrigel implantation, the combination therapy (F+H) led to increased total, and specifically M2-like, macrophage infiltration versus control and VEGF-A plugs, correlating with the angiogenic response. In contrast, VEGF-A preferential recruited M1-type macrophages. In agreement with a direct role of M2-like macrophages in F+H-induced vessel growth, clodronate radically decreased angiogenesis. Further, DC101 reduced F+H-induced angiogenesis, without altering macrophage infiltration, revealing macrophage-derived VEGF-A as a crucial determinant of tissue responsiveness. Similarly, increased cardiac M2-like macrophage infiltration was found following F+H therapy post-MI, with strong correlation between macrophage levels and angiogenic and arteriogenic responses. In conclusion, M2-like macrophages play a decisive role, linked to VEGF-A production, in regulation of tissue responsiveness to angiogenic therapies including the combination of F+H. Our data suggest that future attempts at therapeutic revascularization in ischemic patients might benefit from coupling targeted growth factor delivery with either direct or indirect approaches to recruit pro-angiogenic macrophages in order to maximize therapeutic angiogenic/arteriogenic responses.

• Authors: Virginie Barbay, Mahmoud Houssari, Malik Mekki, Sebastien Banquet, Florence Edwards-Lévy, Jean-Paul Henry, Anais Dumesnil, Sahil Adriouch, Christian Thuillez, Vincent Richard, Ebba Brakenhielm
• Journal: Angiogenesis (Angiogenesis) Vol. 18 Issue 2 Pg. 191-200 (Apr 2015) ISSN: 1573-7209 [Electronic] Germany
• PMID: 25537851 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Fibroblast Growth Factor 2
• Hepatocyte Growth Factor

Topics

• Animals
• Fibroblast Growth Factor 2 (pharmacology, therapeutic use)
• Hepatocyte Growth Factor (pharmacology, therapeutic use)
• Macrophages (drug effects)
• Male
• Mice
• Rats
• Rats, Wistar