title: CC-chemokine class inhibition attenuates pathological angiogenesis while preserving physiological angiogenesis.
abstract: 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 angiogenesisviaconditional 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.
authors.affiliation: Heart Research Institute, Newtown, New South Wales, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Anisyah
authors.initials: A
authors.lastname: Ridiandries
authors.affiliation: Heart Research Institute, Newtown, New South Wales, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Joanne T M
authors.initials: JT
authors.lastname: Tan
authors.affiliation: Heart Research Institute, Newtown, New South Wales, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Dhanya
authors.initials: D
authors.lastname: Ravindran
authors.affiliation: Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.|Vascular Biology Research Centre, Department of Surgery, Westmead Hospital, University of Sydney, Westmead, New South Wales, Australia; and.
authors.forename: Helen
authors.initials: H
authors.lastname: Williams
authors.affiliation: Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.|Vascular Biology Research Centre, Department of Surgery, Westmead Hospital, University of Sydney, Westmead, New South Wales, Australia; and.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Medbury
authors.affiliation: Department of Anatomy and Histology, School of Medical Sciences, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Laura
authors.initials: L
authors.lastname: Lindsay
authors.affiliation: Heart Research Institute, Newtown, New South Wales, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Clare
authors.initials: C
authors.lastname: Hawkins
authors.affiliation: Heart Research Institute, Newtown, New South Wales, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Hamish C G
authors.initials: HC
authors.lastname: Prosser
authors.affiliation: Heart Research Institute, Newtown, New South Wales, Australia; bursillc@hri.org.au.|Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Christina A
authors.initials: CA
authors.lastname: Bursill
mesh_terms: D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D019742:Chemokines, CC / Q000037:antagonists & inhibitors*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D014759:Viral Envelope Proteins / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D019742:Chemokines, CC; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D014759:Viral Envelope Proteins; C072495:immunodominant protein p35, vaccinia virus
keywords: VEGF; inflammation; ischemia