title: RANTES/CCL5 mediated-biological effects depend on the syndecan-4/PKCα signaling pathway.
abstract: The perpetuation of angiogenesis is involved in certain chronic inflammatory diseases. The accelerated neovascularisation may result from an inflammatory status with a response of both endothelial cells and monocytes to inflammatory mediators such as chemokines. We have previously described in vitro and in vivo the pro-angiogenic effects of the chemokine Regulated on Activation, Normal T Cell Expressed and Secreted (RANTES)/CCL5. The effects of RANTES/CCL5 may be related to its binding to G protein-coupled receptors and to proteoglycans such as syndecan-1 and -4. The aim of this study was to evaluate the functionality of syndecan-4 as a co-receptor of RANTES/CCL5 by the use of mutated syndecan-4 constructs. Our data demonstrate that site-directed mutations in syndecan-4 modify RANTES/CCL5 biological activities in endothelial cells. The SDC4S179A mutant, associated with an induced protein kinase C (PKC)α activation, leads to higher RANTES/CCL5 pro-angiogenic effects, whereas the SDC4L188QQ and the SDC4A198del mutants, leading to lower phosphatidylinositol 4,5-bisphosphate (PIP2) binding or to lower PDZ protein binding respectively, are associated with reduced RANTES/CCL5 cellular effects. Moreover, our data highlight that the intracellular domain of SDC-4 is involved in RANTES/CCL5-induced activation of the PKCα signaling pathway and biological effect. As RANTES/CCL5 is involved in various physiopathological processes, the development of a new therapeutic strategy may be reliant on the mechanism by which RANTES/CCL5 exerts its biological activities, for example by targeting the binding of the chemokine to its proteoglycan receptor.
authors.affiliation: Inserm U1148, Laboratory for Vascular Translational Science, Bio-ingénierie Cardio-vasculaire, UFR SMBH, Université Paris 13, Sorbonne Paris Cité, 74 rue Marcel Cachin, 93017 Bobigny, France.
authors.forename: Loïc
authors.initials: L
authors.lastname: Maillard
authors.affiliation: Laboratory of Molecular Pharmacology, Biosignal Research Center, Kobe University, Kobe 657-8501, Japan.
authors.forename: Naoaki
authors.initials: N
authors.lastname: Saito
authors.affiliation: Inserm U1148, Laboratory for Vascular Translational Science, Bio-ingénierie Cardio-vasculaire, UFR SMBH, Université Paris 13, Sorbonne Paris Cité, 74 rue Marcel Cachin, 93017 Bobigny, France.
authors.forename: Hanna
authors.initials: H
authors.lastname: Hlawaty
authors.affiliation: Inserm U1148, Laboratory for Vascular Translational Science, Bio-ingénierie Cardio-vasculaire, UFR SMBH, Université Paris 13, Sorbonne Paris Cité, 74 rue Marcel Cachin, 93017 Bobigny, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Friand
authors.affiliation: Inserm U1148, Laboratory for Vascular Translational Science, Bio-ingénierie Cardio-vasculaire, UFR SMBH, Université Paris 13, Sorbonne Paris Cité, 74 rue Marcel Cachin, 93017 Bobigny, France.
authors.forename: Nadine
authors.initials: N
authors.lastname: Suffee
authors.affiliation: Inserm U1148, Laboratory for Vascular Translational Science, Bio-ingénierie Cardio-vasculaire, UFR SMBH, Université Paris 13, Sorbonne Paris Cité, 74 rue Marcel Cachin, 93017 Bobigny, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Chmilewsky
authors.affiliation: Inserm U1148, Laboratory for Vascular Translational Science, Bio-ingénierie Cardio-vasculaire, UFR SMBH, Université Paris 13, Sorbonne Paris Cité, 74 rue Marcel Cachin, 93017 Bobigny, France.
authors.forename: Oualid
authors.initials: O
authors.lastname: Haddad
authors.affiliation: Inserm U1148, Laboratory for Vascular Translational Science, Bio-ingénierie Cardio-vasculaire, UFR SMBH, Université Paris 13, Sorbonne Paris Cité, 74 rue Marcel Cachin, 93017 Bobigny, France Laboratoire de Biochimie, Hôpital Jean Verdier, AP-HP, 93143 Bondy, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Laguillier
authors.affiliation: Inserm U1148, Laboratory for Vascular Translational Science, Bio-ingénierie Cardio-vasculaire, UFR SMBH, Université Paris 13, Sorbonne Paris Cité, 74 rue Marcel Cachin, 93017 Bobigny, France Laboratoire de Biochimie, Hôpital Jean Verdier, AP-HP, 93143 Bondy, France.
authors.forename: Erwan
authors.initials: E
authors.lastname: Guyot
authors.affiliation: Laboratory of Molecular Pharmacology, Biosignal Research Center, Kobe University, Kobe 657-8501, Japan.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Ueyama
authors.affiliation: Inserm U1148, Laboratory for Vascular Translational Science, Bio-ingénierie Cardio-vasculaire, UFR SMBH, Université Paris 13, Sorbonne Paris Cité, 74 rue Marcel Cachin, 93017 Bobigny, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Oudar
authors.affiliation: Inserm U1148, Laboratory for Vascular Translational Science, Bio-ingénierie Cardio-vasculaire, UFR SMBH, Université Paris 13, Sorbonne Paris Cité, 74 rue Marcel Cachin, 93017 Bobigny, France Laboratoire de Biochimie, Hôpital Jean Verdier, AP-HP, 93143 Bondy, France.
authors.forename: Angela
authors.initials: A
authors.lastname: Sutton
authors.affiliation: Inserm U1148, Laboratory for Vascular Translational Science, Bio-ingénierie Cardio-vasculaire, UFR SMBH, Université Paris 13, Sorbonne Paris Cité, 74 rue Marcel Cachin, 93017 Bobigny, France Laboratoire de Biochimie, Hôpital Jean Verdier, AP-HP, 93143 Bondy, France nathalie.charnaux@jvr.aphp.fr.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Charnaux
keywords: Chemokine; Endothelial cell; PKC; RANTES/CCL5; Syndecan-4