The Heart Research Institute, Sydney, New South Wales, Australia.
Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
FASEB J. 2019 Dec;33(12):13423-13434. doi: 10.1096/fj.201900232RR. Epub 2019 Oct 1.
M3 is a broad-spectrum chemokine-binding protein that inactivates inflammatory chemokines, including CCL2, CCL5, and CXCL1. The aim of this study was to compare whether M3 could inhibit angiogenesis driven by inflammation or ischemia. Here, apolipoprotein E mice were injected with adenoviral M3 (AdM3) or control adenoviral green fluorescent protein (AdGFP) 3 d prior to stimulating angiogenesis using 2 established models that distinctly represent inflammatory or ischemia-driven angiogenesis, namely the periarterial femoral cuff and hind limb ischemia. AdM3 reduced intimal thickening, adventitial capillary density, and macrophage accumulation in femoral arteries 21 d after periarterial femoral cuff placement compared with AdGFP-treated mice ( < 0.05). AdM3 also reduced mRNA expression of proangiogenic VEGF, inflammatory markers IL-6 and IL-1β, and vascular smooth muscle cell (VSMC)-activated synthetic markers Krüppel-like family of transcription factor 4 (KLF4) and platelet-derived growth factor receptor β (PDGFRβ) in the inflammatory cuff model. In contrast, capillary density, VSMC content, blood flow perfusion, and VEGF gene expression were unaltered between groups in skeletal muscle following hind limb ischemia. , AdM3 significantly reduced human microvascular endothelial cell 1 proliferation, migration, and tubule formation by ∼17, 71.3, and 8.7% ( < 0.05) in macrophage-conditioned medium associating with reduced VEGF and hypoxia-inducible factor 1α mRNA but not in hypoxia (1% O). Compared with AdGFP, AdM3 also inhibited VSMC proliferation and migration and reduced mRNA expression of KLF4 and PDGFRβ under inflammatory conditions. In contrast, AdM3 had no effect on VSMC processes in response to hypoxia . Our findings show that broad-spectrum inhibition of inflammatory chemokines by M3 inhibits inflammatory-driven but not ischemia-driven angiogenesis, presenting a novel strategy for the treatment of diseases associated with inflammatory-driven angiogenesis.-Ravindran, D., Cartland, S. P., Bursill, C. A., Kavurma, M. M. Broad-spectrum chemokine inhibition blocks inflammation-induced angiogenesis, but preserves ischemia-driven angiogenesis.
M3 是一种广谱趋化因子结合蛋白，可使炎症趋化因子（包括 CCL2、CCL5 和 CXCL1）失活。本研究旨在比较 M3 是否能抑制炎症或缺血引起的血管生成。在此，载脂蛋白 E 小鼠在使用两种明显代表炎症或缺血驱动血管生成的已建立模型（即股动脉周 cuff 和后肢缺血）刺激血管生成前 3 天注射腺病毒 M3（AdM3）或对照腺病毒绿色荧光蛋白（AdGFP）。与 AdGFP 处理的小鼠相比，AdM3 可减少股动脉周 cuff 放置后 21 天的内膜增厚、血管外膜毛细血管密度和巨噬细胞积聚（<0.05）。AdM3 还降低了炎症 cuff 模型中促血管生成 VEGF、炎症标志物 IL-6 和 IL-1β 以及血管平滑肌细胞（VSMC）激活的合成标志物 Kruppel 样转录因子家族 4（KLF4）和血小板衍生生长因子受体 β（PDGFRβ）的 mRNA 表达。相比之下，后肢缺血后骨骼肌的毛细血管密度、VSMC 含量、血流灌注和 VEGF 基因表达在各组之间没有改变。然而，在巨噬细胞条件培养基中，AdM3 显著降低了人微血管内皮细胞 1 的增殖、迁移和小管形成，分别降低了约 17%、71.3%和 8.7%（<0.05），同时降低了 VEGF 和缺氧诱导因子 1α mRNA，但在缺氧（1%O）中没有降低。与 AdGFP 相比，AdM3 还抑制了炎症条件下 VSMC 的增殖和迁移，并降低了 KLF4 和 PDGFRβ 的 mRNA 表达。相比之下，AdM3 对缺氧引起的 VSMC 过程没有影响。我们的研究结果表明，M3 对炎症趋化因子的广谱抑制抑制了炎症驱动的但不是缺血驱动的血管生成，为治疗与炎症驱动的血管生成相关的疾病提供了一种新策略。-Ravindran, D., Cartland, S. P., Bursill, C. A., Kavurma, M. M. 广谱趋化因子抑制阻断炎症诱导的血管生成，但保留缺血诱导的血管生成。
