INSERM, U698, Bio-ingenierie Cardiovasculaire; UFR SMBH, Université Paris 13, Sorbonne Paris Cité, 74 Rue Marcel Cachin, 93017, Bobigny, France.
Angiogenesis. 2012 Dec;15(4):727-44. doi: 10.1007/s10456-012-9285-x. Epub 2012 Jun 30.
Atherosclerosis involves angiogenesis and inflammation with the ability of endothelial cells and monocytes to respond to chemokines. We addressed here by in vitro and in vivo approaches, the role of the chemokine Regulated on Activation, Normal T Cell Expressed and Secreted (RANTES)/CCL5 on angiogenesis through its receptors CCR1, CCR5, syndecan-1 (SDC-1), syndecan-4 (SDC-4) and CD-44. Our data demonstrate that RANTES/CCL5 is pro-angiogenic in a rat subcutaneous model. This RANTES/CCL5-activity may be related to the in vitro promotion of endothelial cell migration, spreading and neo-vessel formation. RANTES/CCL5-mediated angiogenesis depends at least partly on Vascular Endothelial Growth Factor (VEGF) secretion by endothelial cells, since this effect is decreased when endothelial cells are incubated with anti-VEGF receptor antibodies. RANTES/CCL5-induced chemotaxis is mediated by matrix metalloproteinase-9. We demonstrate that specific receptors of RANTES/CCL5 such as G protein-coupled receptors CCR1 and CCR5, and heparan sulfate proteoglycans, SDC-1, SDC-4 or CD-44, play a major role in RANTES/CCL5-induced angiogenic effects. By the use of two RANTES/CCL5 mutants, [E66A]-RANTES/CCL5 with impaired ability to oligomerize, and [44AANA47]-RANTES/CCL5 mutated in the main RANTES/CCL5-glycosaminoglycan (GAG) binding site, we demonstrate that chemokine oligomerization and binding to GAGs are essential in RANTES/CCL5-induced angiogenic effects. According to these results, new therapeutic strategies based on RANTES/CCL5 can be proposed for neo-angiogenesis after vascular injury. Mutants of RANTES/CCL5 may also represent an innovative approach to prevent the angiogenesis associated with the formation of atherosclerotic plaque.
动脉粥样硬化涉及血管生成和炎症，内皮细胞和单核细胞能够对趋化因子做出反应。我们通过体外和体内方法研究了趋化因子调节激活正常 T 细胞表达和分泌（RANTES）/CCL5 通过其受体 CCR1、CCR5、硫酸乙酰肝素蛋白聚糖-1（SDC-1）、硫酸乙酰肝素蛋白聚糖-4（SDC-4）和 CD-44 对血管生成的作用。我们的数据表明，RANTES/CCL5 在大鼠皮下模型中具有促血管生成作用。这种 RANTES/CCL5 活性可能与体外促进内皮细胞迁移、扩展和新血管形成有关。RANTES/CCL5 介导的血管生成至少部分依赖于内皮细胞分泌血管内皮生长因子（VEGF），因为当内皮细胞用抗 VEGF 受体抗体孵育时，这种作用会降低。RANTES/CCL5 诱导的趋化作用由基质金属蛋白酶-9 介导。我们证明，RANTES/CCL5 的特定受体，如 G 蛋白偶联受体 CCR1 和 CCR5，以及硫酸乙酰肝素蛋白聚糖 SDC-1、SDC-4 或 CD-44，在 RANTES/CCL5 诱导的血管生成作用中起主要作用。通过使用两种 RANTES/CCL5 突变体，即寡聚能力受损的[E66A]-RANTES/CCL5 和主要 RANTES/CCL5-糖胺聚糖（GAG）结合位点发生突变的[44AANA47]-RANTES/CCL5，我们证明趋化因子寡聚化和与 GAG 的结合对于 RANTES/CCL5 诱导的血管生成作用至关重要。根据这些结果，可以针对血管损伤后的新血管生成提出基于 RANTES/CCL5 的新治疗策略。RANTES/CCL5 的突变体也可能代表一种新的方法来防止与动脉粥样硬化斑块形成相关的血管生成。
