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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1426.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Expression of Vascular Endothelial Growth Factor, Stromal Cell-Derived Factor-1, and CXCR4 in Human Limb Muscle With Acute and Chronic Ischemia

Vincent van Weel; Leonard Seghers; Margreet R. de Vries; Esther J. Kuiper; Reinier O. Schlingemann; Ingeborg M. Bajema; Jan H.N. Lindeman; Pien M. Delis-van Diemen; Victor W.M. van Hinsbergh; J. Hajo van Bockel; Paul H.A. Quax

From Gaubius Laboratory, TNO Quality of Life (V.v.W., L.S., M.R.d.V., J.H.N.L., P.H.A.Q.), Leiden, the Netherlands; Department of Surgery (V.v.W., L.S., J.H.N.L., P.H.A.Q.), Leiden University Medical Center, Leiden, the Netherlands; Department Ophtalmology (E.J.K., R.O.S.), Amsterdam Medical Center, Amsterdam, the Netherlands; Department of Pathology (I.B.), Leiden University Medical Center; Department of Pathology (P.M.D.-v.D.), VU University Medical Center, Amsterdam, the Netherlands; Department of Physiology (V.W.M.H.), Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands.

Correspondence to Dr P.H.A. Quax, Gaubius Laboratory TNO-Quality of Life, P.O. Box 2215, 2301CE Leiden, the Netherlands. E-mail paul.quax{at}tno.nl

Objective— Vascular endothelial growth factor (VEGF)-induced stromal cell-derived factor-1 (SDF-1) has been implicated in angiogenesis in ischemic tissues by recruitment of CXCR4-positive bone marrow-derived circulating cells with paracrine functions in preclinical models. Here, evidence for this is provided in patients with peripheral artery disease.

Methods and Results— Expression patterns of VEGF, SDF-1, and CXCR4 were studied in amputated limbs of 16 patients. VEGF-A was expressed in vascular structures and myofibers. SDF-1 was expressed in endothelial and subendothelial cells, whereas CXCR4 was expressed in proximity to capillaries. VEGF-A, SDF-1, and CXCR4 expressions were generally decreased in ischemic muscle as compared with nonischemic muscle in patients with chronic ischemia (0.41-fold, 0.97-fold, and 0.54-fold induction [medians], respectively), whereas substantially increased in 2 patients with acute-on-chronic ischemia (3.5- to 65.8-fold, 3.9- to 19.0-fold, and 4.1- to 30.6-fold induction, respectively). Furthermore, these gene expressions strongly correlated with capillary area. Only acute ischemic tissue displayed a high percentage of hypoxia-inducible factor-1–positive nuclei.

Conclusions— These data suggest that VEGF and SDF-1 function as pro-angiogenic factors in patients with ischemic disease by perivascular retention of CXCR4-positive cells. Furthermore, these genes are downregulated in chronic ischemia as opposed to upregulated in more acute ischemia. The VEGF-SDF-1-CXCR4 pathway is a promising target to treat chronic ischemic disease.

In amputated limbs of patients with peripheral artery disease, expression patterns of VEGF, SDF-1, and CXCR4 suggest a coordinated role of these factors in ischemia-induced angiogenesis, which were downregulated in chronic ischemia versus upregulated in more acute ischemia. This pathway is a promising target to treat chronic ischemic disease.

Key Words: peripheral artery disease • angiogenesis • ischemia • VEGF • SDF-1

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