CD146 short isoform increases the proangiogenic potential of endothelial progenitor cells in vitro and in vivo.
BACKGROUND
CD146, a transmembrane immunoglobulin mainly expressed at the intercellular junction of endothelial cells, is involved in cell-cell cohesion, paracellular permeability, monocyte transmigration and angiogenesis. CD146 exists as 2 isoforms, short (sh) and long (lg), but which isoform is involved remains undefined.


OBJECTIVE
The recently described role of CD146 in angiogenesis prompted us to investigate which isoform was involved in this process in human late endothelial progenitors (EPCs), with the objective of increasing their proangiogenic potential.


RESULTS
Immunofluorescence experiments showed that, in subconfluent EPCs, shCD146 was localized in the nucleus and at the migrating edges of the membrane, whereas lgCD146 was intracellular. In confluent cells, shCD146 was redistributed at the apical membrane and lgCD146 was directed toward the junction. In contrast to lgCD146, shCD146 was overexpressed in EPCs as compared to mature endothelial cells and upregulated by vascular endothelial growth factor and SDF-1 (stromal cell-derived factor 1). Study of the properties of both isoforms in vitro provided evidence that shCD146 was involved in EPC adhesion to activated endothelium, migration, and proliferation, with a paracrine secretion of interleukin-8 or angiopoietin 2, whereas lgCD146 was implicated in stabilization of capillary-like structures in Matrigel and transendothelial permeability. In an animal model of hindlimb ischemia, transplantation of shCD146-modified EPCs selectively promoted both EPC engraftment and blood flow.


CONCLUSIONS
Altogether, these findings establish that CD146 isoforms display distinct functions in vessels regeneration. Selective improvement of therapeutic angiogenesis by shCD146 overexpression suggests a potential interest of shCD146-transduced EPCs for the treatment of peripheral ischemic disease.
Kebir
Abdeldjalil
A
Institut National de la Santé et de la Recherche Médicale UMR-S 608, Physiopathologie de l'Endothélium, Université de la Méditerranée, UFR Pharmacie, Marseille, France.
Harhouri
Karim
K
Guillet
Benjamin
B
Liu
Jia Wei
JW
Foucault-Bertaud
Alexandrine
A
Lamy
Edouard
E
Kaspi
Elise
E
Elganfoud
Nadia
N
Vely
Frédéric
F
Sabatier
Florence
F
Sampol
José
J
Pisano
Pascale
P
Kruithof
Egbert K O
EK
Bardin
Nathalie
N
Dignat-George
Françoise
F
Blot-Chabaud
Marcel
M
D000818:Animals; D051929:CD146 Antigen / Q000096:biosynthesis / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000502:physiology* / Q000637:transplantation; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D007511:Ischemia / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D051379:Mice; D018919:Neovascularization, Physiologic / Q000502:physiology*; D020033:Protein Isoforms / Q000096:biosynthesis / Q000502:physiology; D033581:Stem Cell Transplantation / Q000379:methods; D013234:Stem Cells / Q000502:physiology*
D051929:CD146 Antigen; D020033:Protein Isoforms