Caveolin plays a central role in endothelial progenitor cell mobilization and homing in SDF-1-driven postischemic vasculogenesis.
When neovascularization is triggered in ischemic tissues, angiogenesis but also (postnatal) vasculogenesis is induced, the latter requiring the mobilization of endothelial progenitor cells (EPC) from the bone marrow. Caveolin, the structural protein of caveolae, was recently reported to directly influence the angiogenic process through the regulation of the vascular endothelial growth factor (VEGF)/nitric oxide pathway. In this study, using caveolin-1 null mice (Cav(-/-)), we examined whether caveolin was also involved in the EPC recruitment in a model of ischemic hindlimb. Intravenous infusion of Sca-1(+) Lin(-) progenitor cells, but not bone marrow transplantation, rescued the defective neovascularization in Cav(-/-) mice, suggesting a defect in progenitor mobilization. The adhesion of Cav(-/-) EPC to bone marrow stromal cells indeed appeared to be resistant to the otherwise mobilizing SDF-1 (Stromal cell-Derived Factor-1) exposure because of a defect in the internalization of the SDF-1 cognate receptor CXCR4. Symmetrically, the attachment of Cav(-/-) EPC to SDF-1-presenting endothelial cells was significantly increased. Finally, EPC transduction with caveolin small interfering RNA reproduced this advantage in vitro and, importantly, led to a more extensive rescue of the ischemic hindlimb after intravenous infusion (versus sham-transfected EPC). These results underline the critical role of caveolin in ensuring the caveolae-mediated endocytosis of CXCR4, regulating both the SDF-1-mediated mobilization and peripheral homing of progenitor cells in response to ischemia. In particular, a transient reduction in caveolin expression was shown to therapeutically increase the engraftment of progenitor cells.
Sbaa
Elhem
E
Unit of Pharmacology and Therapeutics, University of Louvain Medical School, Brussels, Belgium.
Dewever
Julie
J
Martinive
Philippe
P
Bouzin
Caroline
C
Frérart
Françoise
F
Balligand
Jean-Luc
JL
Dessy
Chantal
C
Feron
Olivier
O
D000818:Animals; D001854:Bone Marrow Cells; D016026:Bone Marrow Transplantation; D051242:Caveolin 1 / Q000172:deficiency / Q000378:metabolism*; D002448:Cell Adhesion; D002465:Cell Movement; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000097:blood / Q000378:metabolism*; D042783:Endothelial Cells; D006614:Hindlimb / Q000098:blood supply*; D007511:Ischemia / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D012039:Regional Blood Flow; D013234:Stem Cells; D017154:Stromal Cells
D051242:Caveolin 1; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse