ABSTRACT
OBJECTIVES: A wide range of compounds inhibit formation of new blood vessels in a variety of models, accompanied by decreases in pro-angiogenic cytokines. The authors sought a surrogate marker for the complex process of neovascularization by correlating inhibition of cytokine production with anti-angiogenic effect. METHODS: Three anti-angiogenic compounds, clotrimazole (120 mg kg(-1) day(-1)), thalidomide (100 mg kg(-1) day(-1)), and rosiglitazone (10 mg kg(-1) day(-1)), were used to inhibit angiogenesis developing over 9 days, in sponges implanted subcutaneously in Swiss mice. Angiogenesis was assessed by hemoglobin content and by histology. Content of cytokines in implants was measured by specific immunoassays and accumulation of neutrophils or macrophages in implants by measuring myeloperoxidase or N-acetylglucosaminidase activity, respectively. RESULTS: These compounds caused equal inhibition of angiogenesis (about 40%). However, implant levels of vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF-alpha) or the macrophage chemoattractant cytokine, CCL2/MCP-1/JE, and accumulation of macrophages were more variably inhibited. Only the neutrophil chemokine, CXCL2/KC, was inhibited equally by the three compounds, in this model. CONCLUSIONS: Anti-angiogenic effect was most clearly and closely correlated with levels of the chemokine KC. Thus, measurement of the chemokine KC might provide an adequate surrogate marker for the functional process of neovascularization in our model.