A novel CXCR4 antagonist derived from human SDF-1beta enhances angiogenesis in ischaemic mice.

ABSTRACT:

Aims

The effects on angiogenesis of a novel CXC chemokine receptor 4 (CXCR4) antagonist, SDF-1betaP2G, derived from human stromal cell-derived factor-1beta (SDF-1beta), were examined in a model of hind limb ischaemia in mice.

Methods and results

The antagonistic activities of SDF-1betaP2G against CXCR4 were evaluated in vitro and in vivo and compared with phosphate-buffered saline and AMD3100 (a small bicyclam antagonist of SDF-1). Angiogenesis, muscle regeneration and the expression of pro-angiogenic factors were evaluated in ischaemic gastrocnemius muscles. Distant toxic effects of SDF-1betaP2G were evaluated by inflammatory and apoptotic markers. SDF-1betaP2G induced CXCR4 internalization and competitively inhibited the chemotaxis of SDF-1beta but did not mediate migration, calcium influx, or the phosphorylation of Akt and extracellular signal-regulated kinase in cultured T-lymphoblastic leukaemia cells or H9C2 cells. SDF-1betaP2G enhanced blood flow, angiogenesis, and muscle regeneration in ischaemic hind limbs, and the enhancement was significantly better than that of AMD3100. Markers of angiogenesis and progenitor cell migration, including phosphorylated Akt, vascular endothelial growth factor (VEGF), SDF-1 and CXCR4, were up-regulated by SDF-1betaP2G and co-localized with CD31-positive cells. Neutralization of VEGF with its specific antibody abolished SDF-1betaP2G-induced blood reperfusion and angiogenesis. No apparent inflammatory and apoptotic effects were found in heart, liver, kidneys, and testes after SDF-1betaP2G administration.

Conclusion

Our findings indicate that the novel CXCR4 antagonist, SDF-1betaP2G, can efficiently enhance ischaemic angiogenesis, blood flow restoration, and muscle regeneration without apparent adverse effects, most likely through a VEGF-dependent pathway.

SUBMITTER: Tan Y 

PROVIDER: S-EPMC2682612 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature