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Cardiovascular Research 2006 69(4):925-935; doi:10.1016/j.cardiores.2005.12.005
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Copyright © 2006, European Society of Cardiology

Efficacy of systemic administration of SDF-1 in a model of vascular insufficiency: Support for an endothelium-dependent mechanism

Andrew N. Carra, Brian W. Howarda, Hsiao T. Yangb, Elaine Eby-Wilkensa, Paula Loosa, Alex Varbanova, Angela Qua, Jeffrey P. DeMutha, Michael G. Davisa, Alan Proiac, Ronald L. Terjungb and Kevin G. Petersa,*

aProcter and Gamble Pharmaceuticals, Cardiovascular Research Division, Health Care Research Center, 8700 Mason Montgomery Rd, Box 1064, Mason, Ohio, 45040, United States
bDepartment of Biomedical Sciences, University of Missouri, E102 Veterinary Medicine Bldg. Columbia, Missouri, 65211, United States
cDepartment of Pathology, Duke University Medical Center, Room 3078 Duke Hospital South, Durham, North Carolina, 27710, United States

* Corresponding author. Tel.: +1 513 622 0834; fax: +1 513 622 1433. Email address: peters.kg{at}pg.com

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.

Conclusion: 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.

KEYWORDS Angiogenesis; Blood flow; Collateral circulation; Endothelial factors

Time for primary review 22 days


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