Efficacy of systemic administration of SDF-1 in a model of vascular insufficiency: support for an endothelium-dependent mechanism.
OBJECTIVE
Studies have reported that administration of stromal cell-derived factor-1 (SDF-1), the ligand for the G-protein coupled receptor CXCR4, increased collateral blood flow in a mouse model of vascular insufficiency via recruitment of endothelial precursor cells (EPC). The present study investigated the contribution of mature endothelial cells in the actions of SDF-1.


METHODS
The regulation of SDF-1 and CXCR4 was examined in the rat cornea cauterization (CC) and aortic ring (AR) model. The functional significance of the SDF-1/CXCR4 pathway was explored in cultured endothelial cells, the AR model, and on collateral blood flow in a rat model of vascular insufficiency.


RESULTS
In the present study, the CXCR4 transcript was dramatically upregulated in the rat CC and AR explants, systems containing and lacking bone marrow-derived EPCs, respectively. Addition of AMD3100, a selective CXCR4 antagonist, had no effect on vessel growth in the AR alone, but completely inhibited SDF-1 mediated increases in vascular sprouting. In cultured endothelial cells, SDF-1 alone or in combination with vascular endothelial growth factor (VEGF) significantly enhanced cell survival and migration. Finally, systemic administration of SDF-1 in a rat model of arterial insufficiency enhanced collateral blood flow above vehicle control and equal to that of VEGF after 2 weeks of treatment.


CONCLUSIONS
These studies support activation of the SDF-1/CXCR4 axis as a means to promote blood vessel growth and enhance collateral blood flow, at least in part, via direct effects on vascular endothelial cells.
Carr
Andrew N
AN
Procter and Gamble Pharmaceuticals, Cardiovascular Research Division, Health Care Research Center, Mason, Ohio 45040 USA.
Howard
Brian W
BW
Yang
Hsiao T
HT
Eby-Wilkens
Elaine
E
Loos
Paula
P
Varbanov
Alex
A
Qu
Angela
A
DeMuth
Jeffrey P
JP
Davis
Michael G
MG
Proia
Alan
A
Terjung
Ronald L
RL
Peters
Kevin G
KG
D000818:Animals; D001011:Aorta; D015415:Biomarkers / Q000032:analysis; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use; D003097:Collateral Circulation; D003315:Cornea / Q000098:blood supply; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D006614:Hindlimb / Q000098:blood supply; D007150:Immunohistochemistry / Q000379:methods; D066298:In Vitro Techniques; D023421:Models, Animal; D009389:Neovascularization, Pathologic; D020411:Oligonucleotide Array Sequence Analysis; D016491:Peripheral Vascular Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D012039:Regional Blood Flow / Q000187:drug effects
D015415:Biomarkers; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D012333:RNA, Messenger; D019718:Receptors, CXCR4