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.