Increasing evidence shows that
CC-chemokines promote inflammatory-driven angiogenesis, with little to no effect on
hypoxia-mediated angiogenesis. Inhibition of the
CC-chemokine class may therefore affect angiogenesis differently depending on the pathophysiological context. We compared the effect of
CC-chemokine inhibition in inflammatory and physiological conditions. In vitro, the broad-spectrum
CC-chemokine inhibitor "35K" inhibited inflammatory-induced endothelial cell proliferation, migration, and tubulogenesis, with more modest effects in
hypoxia. In vivo, adenoviruses were used to overexpress 35K (Ad35K) and GFP (AdGFP, control virus). Plasma
chemokine activity was suppressed by Ad35K in both models. In the periarterial femoral cuff model of inflammatory-driven angiogenesis, overexpression of 35K inhibited adventitial neovessel formation compared with control AdGFP-infused mice. In contrast, 35K preserved neovascularization in the hindlimb
ischemia model and had no effect on physiological neovascularization in the chick chorioallantoic membrane assay. Mechanistically, 2 key
angiogenic proteins (
VEGF and
hypoxia-inducible factor-1α) were conditionally regulated by 35K, such that expression was inhibited in
inflammation but was unchanged in
hypoxia. In conclusion,
CC-chemokine inhibition by 35K suppresses inflammatory-driven angiogenesis while preserving physiological
ischemia-mediated angiogenesis via conditional regulation of
VEGF and
hypoxia-inducible factor-1α.
CC-chemokine inhibition may be an alternative therapeutic strategy for suppressing diseases associated with inflammatory angiogenesis without inducing the side effects caused by global inhibition.- Ridiandries, A., Tan, J. T. M., Ravindran, D., Williams, H., Medbury, H. J., Lindsay, L., Hawkins, C., Prosser, H. C. G., Bursill, C. A.
CC-chemokine class inhibition attenuates
pathological angiogenesis while preserving physiological angiogenesis.