Gene transfer of stromal cell-derived factor-1alpha enhances ischemic vasculogenesis and angiogenesis via vascular endothelial growth factor/endothelial nitric oxide synthase-related pathway: next-generation chemokine therapy for therapeutic neovascularization.
BACKGROUND
Stromal cell-derived factor-1alpha (SDF-1alpha) is implicated as a chemokine for endothelial progenitor cells (EPCs). We therefore hypothesized that SDF-1alpha gene transfer would induce therapeutic neovascularization in vivo by functioning as a chemokine of EPC.


RESULTS
To examine SDF-1alpha-induced mobilization of EPC, we used bone marrow-transplanted mice whose blood cells ubiquitously express beta-galactosidase (LacZ). We produced unilateral hindlimb ischemia in the mice and transfected them with plasmid DNA encoding SDF-1alpha or empty plasmids into the ischemic muscles. SDF-1alpha gene transfer mobilized EPCs into the peripheral blood, augmented recovery of blood perfusion to the ischemic limb, and increased capillary density associated with partial incorporation of LacZ-positive cells into the capillaries of the ischemic limb, suggesting that SDF-1alpha induced vasculogenesis and angiogenesis. SDF-1alpha gene transfer did not affect ischemia-induced expression of vascular endothelial growth factor (VEGF) but did enhance Akt and endothelial nitric oxide synthase (eNOS) activity. Blockade of VEGF or NOS prevented all such SDF-1alpha-induced effects.


CONCLUSIONS
SDF-1alpha gene transfer enhanced ischemia-induced vasculogenesis and angiogenesis in vivo through a VEGF/eNOS-related pathway. This strategy might become a novel chemokine therapy for next generation therapeutic neovascularization.
Hiasa
Ken-ichi
K
Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan
Ishibashi
Minako
M
Ohtani
Kisho
K
Inoue
Shujiro
S
Zhao
Qingwei
Q
Kitamoto
Shiro
S
Sata
Masataka
M
Ichiki
Toshihiro
T
Takeshita
Akira
A
Egashira
Kensuke
K
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D016026:Bone Marrow Transplantation; D002196:Capillaries / Q000254:growth & development; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000235:genetics*; D002633:Chemotaxis; D004730:Endothelium, Vascular / Q000166:cytology; D015316:Genetic Therapy; D006614:Hindlimb / Q000098:blood supply; D007511:Ischemia / Q000378:metabolism / Q000628:therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D013234:Stem Cells / Q000502:physiology; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D011518:Proto-Oncogene Proteins; D042461:Vascular Endothelial Growth Factor A; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt