Ridiandries Anisyah, Tan Joanne T M, Ravindran Dhanya, Williams Helen, Medbury Heather J, Lindsay Laura, Hawkins Clare, Prosser Hamish C G, Bursill Christina A
Heart Research Institute, Newtown, New South Wales, Australia.
Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
FASEB J. 2017 Mar;31(3):1179-1192. doi: 10.1096/fj.201600540R. Epub 2016 Dec 20.
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. , the broad-spectrum CC-chemokine inhibitor "35K" inhibited inflammatory-induced endothelial cell proliferation, migration, and tubulogenesis, with more modest effects in hypoxia. , 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 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.
越来越多的证据表明，CC趋化因子可促进炎症驱动的血管生成，而对缺氧介导的血管生成几乎没有影响。因此，CC趋化因子类的抑制作用可能会根据病理生理背景对血管生成产生不同的影响。我们比较了CC趋化因子抑制在炎症和生理条件下的作用。广谱CC趋化因子抑制剂“35K”抑制了炎症诱导的内皮细胞增殖、迁移和管状结构形成，在缺氧条件下的作用则较为温和。使用腺病毒过表达35K（Ad35K）和绿色荧光蛋白（AdGFP，对照病毒）。在两种模型中，Ad35K均抑制了血浆趋化因子活性。在炎症驱动的血管生成的股动脉周围袖带模型中，与注入对照AdGFP的小鼠相比，35K的过表达抑制了外膜新血管形成。相反，35K在后肢缺血模型中保留了新血管生成，并且在鸡胚绒毛尿囊膜试验中对生理性新血管生成没有影响。从机制上讲，两种关键的血管生成蛋白（血管内皮生长因子和缺氧诱导因子-1α）受35K的条件性调节，使得其表达在炎症中受到抑制，但在缺氧时保持不变。总之，35K对CC趋化因子的抑制作用抑制了炎症驱动的血管生成，同时通过对血管内皮生长因子和缺氧诱导因子-1α的条件性调节保留了生理性缺血介导的血管生成。CC趋化因子抑制可能是一种替代治疗策略，用于抑制与炎症性血管生成相关的疾病，而不会引发全局抑制所导致的副作用。- 里迪安德里兹，A.，谭，J. T. M.，拉温德兰，D.，威廉姆斯，H.，梅德伯里，H. J.，林赛，L.，霍金斯，C.，普罗瑟，H. C. G.，伯西尔，C. A. CC趋化因子类抑制可减轻病理性血管生成，同时保留生理性血管生成。
