Soluble CD146 displays angiogenic properties and promotes neovascularization in experimental hind-limb ischemia.
CD146, an endothelial molecule involved in permeability and monocyte transmigration, has recently been reported to promote vessel growth. As CD146 is also detectable as a soluble form (sCD146), we hypothesized that sCD146 could stimulate angiogenesis. Experiments of Matrigel plugs in vivo showed that sCD146 displayed chemotactic activity on endogenous endothelial cells, and exogenously injected late endothelial progenitor cells (EPCs). Recruited endothelial cells participated in formation of vascular-like structures. In vitro, sCD146 enhanced angiogenic properties of EPCs, with an increased cell migration, proliferation, and capacity to establish capillary-like structures. Effects were additive with those of vascular endothelial growth factor (VEGF), and sCD146 enhanced VEGFR2 expression and VEGF secretion. Consistent with a proangiogenic role, gene expression profiling of sCD146-stimulated EPCs revealed an up-regulation of endothelial nitric oxide synthase, urokinase plasminogen activator, matrix metalloproteinase 2, and VEGFR2. Silencing membrane-bound CD146 inhibited responses. The potential therapeutic interest of sCD146 was tested in a model of hind limb ischemia. Local injections of sCD146 significantly reduced auto-amputation, tissue necrosis, fibrosis, inflammation, and increased blood flow. Together, these findings establish that sCD146 displays chemotactic and angiogenic properties and promotes efficient neovascularization in vivo. Recombinant human sCD146 might thus support novel strategies for therapeutic angiogenesis in ischemic diseases.
Harhouri
Karim
K
Inserm Unite Mixte de Recherche (UMR)-S 608, Université de la Méditerranée, Unite de Formation et de Recherche Pharmacie, 13385 Marseille, France.
Kebir
Abdeldjalil
A
Guillet
Benjamin
B
Foucault-Bertaud
Alexandrine
A
Voytenko
Serge
S
Piercecchi-Marti
Marie-Dominique
MD
Berenguer
Caroline
C
Lamy
Edouard
E
Vely
Frédéric
F
Pisano
Pascale
P
Ouafik
L'houcine
L
Sabatier
Florence
F
Sampol
José
J
Bardin
Nathalie
N
Dignat-George
Françoise
F
Blot-Chabaud
Marcel
M
D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D015153:Blotting, Western; D051929:CD146 Antigen / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism*; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006614:Hindlimb / Q000098:blood supply* / Q000378:metabolism; D006801:Humans; D007511:Ischemia / Q000209:etiology / Q000378:metabolism* / Q000628:therapy; D008297:Male; D051379:Mice; D008819:Mice, Nude; D018919:Neovascularization, Physiologic; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014945:Wound Healing
D015415:Biomarkers; D051929:CD146 Antigen; D012333:RNA, Messenger