RANTES/CCL5-induced pro-angiogenic effects depend on CCR1, CCR5 and glycosaminoglycans

Abstract

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.

Resveratrol Counteracts Inflammation in Human M1 and M2 Macrophages upon Challenge with 7-Oxo-Cholesterol: Potential Therapeutic Implications in Atherosclerosis

“…The anti-inflammatory and immunomodulatory activities of resveratrol were further confirmed by the inhibition of many chemokines in both subsets, particularly IL-8, MCP-1, CCL3, CCL4, and RANTES and of the growth factors G-CSF and GM-CSF (in M1 cells) and VEGF (in M2 cells). These inflammatory mediators, beside their active role in recruiting leukocytes into inflammatory sites, may stimulate endothelial cell migration, spreading, and neo-vessel formation, thus promoting the angiogenesis associated with the progression of atherosclerotic plaque [28]. The inhibitory effects of resveratrol on TNF- α , IL-6, IL-8, MCP-1, CCL-4, RANTES, and G-CSF in the M1 macrophage subset and on TNF- α , IL-12, IL-8, MCP-1, CCL3, CCL-4, RANTES, and VEGF in M2 macrophages together with metalloproteinases inhibition may be added to a variety of resveratrol antiatherogenic actions, since these molecules are known to be involved in inflammatory responses in arterial walls during progression of atherosclerosis [29].…”

Key Proteins Involved in Spheroid Formation and Angiogenesis in Endothelial Cells After Long-Term Exposure to Simulated Microgravity

“…The chemokine (C-C motif) ligand 5 (also CCL5) is also known as RANTES (regulated on activation, normal T cell expressed and secreted) [33]. It is of interest that the RANTES/CCL5-activity seems to be related to the in vitro promotion of endothelial cell migration, spreading and neo-vessel formation [33].…”

“…It is of interest that the RANTES/CCL5-activity seems to be related to the in vitro promotion of endothelial cell migration, spreading and neo-vessel formation [33]. RANTES/CCL5-mediated angiogenesis depends at least partly on VEGF secretion by ECs [33].…”

Kaposi's Sarcoma-Associated Herpesvirus Kaposin B Induces Unique Monophosphorylation of STAT3 at Serine 727 and MK2-Mediated Inactivation of the STAT3 Transcriptional Repressor TRIM28

“…My studies demonstrate that the constitutively active form of MK2 (MK2EE) in ECs induced 0.4-to 7-fold and 2.4-to 3.4-fold upregulations of CCL5 and IL-6 mRNA, respectively, indicating the relative contribution of MK2-mediated stabilization of CCL5 mRNA in ECs to the upregulation observed when kaposin B was expressed, was small. KS lesions are characterized by chronic inflammation and neoangiogenesis; CCL5 is a potent mediator of both processes (69)(70)(71)(72). The importance of CCL5 in KS pathogenesis is underscored by the fact that both CCL5 and the cognate receptor CCR5 are upregulated in KS but not normal skin (73).…”