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CC‐chemokine class inhibition attenuates pathological angiogenesis while preserving physiological angiogenesis
Author(s) -
Ridiandries Anisyah,
Tan Joanne T. M.,
Ravindran Dhanya,
Williams Helen,
Medbury Heather J.,
Lindsay Laura,
Hawkins Clare,
Prosser Hamish C. G.,
Bursill Christina A.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201600540r
Subject(s) - angiogenesis , chemokine , neovascularization , chorioallantoic membrane , cancer research , ccl7 , biology , inflammation , microbiology and biotechnology , immunology , cxcl10 , chemistry
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‐chemokineclass inhibition attenuates pathological angiogenesis while preserving physiological angiogenesis. FASEB J. 31, 1179–1192 (2017). www.fasebj.org