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Expression of vascular endothelial growth factor, stromal cell-derived factor-1, and CXCR4 in human limb muscle with acute and chronic ischemia

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Author: Weel, V. van · Seghers, L. · Vries, M.R. de · Kuiper, E.J. · Schlingemann, R.O. · Bajema, I.M. · Lindeman, J.H.N. · Delis-Diemen, P.M. van · Hinsbergh, V.W.M. van · Bockel, J.H. van · Quax, P.H.A.
Institution: TNO Kwaliteit van Leven
Source:Arteriosclerosis, Thrombosis, and Vascular Biology, 6, 27, 1426-1432
Identifier: 239989
doi: doi:10.1161/ATVBAHA.107.139642
Keywords: Biology · Biomedical Research · Angiogenesis · Ischemia · Peripheral artery disease · SDF-1 · VEGF · chemokine receptor CXCR4 · hypoxia inducible factor 1alpha · stromal cell derived factor 1 · vasculotropin A · acute disease · adult · aged · angiogenesis · artery disease · article · blood vessel · capillary · chronic disease · controlled study · correlation analysis · down regulation · female · gene control · gene expression · human · human tissue · leg amputation · leg ischemia · leg muscle · limb ischemia · male · muscle cell · muscle ischemia · priority journal · protein expression · protein function · protein induction · upregulation · vascular endothelium · Acute Disease · Aged · Aged, 80 and over · Amputation · Capillaries · Chemokines, CXC · Chronic Disease · Extremities · Female · Humans · Immunohistochemistry · Ischemia · Male · Middle Aged · Muscle, Skeletal · Neovascularization, Physiologic · Peripheral Vascular Diseases · Receptors, CXCR4 · Receptors, Vascular Endothelial Growth Factor · Reverse Transcriptase Polymerase Chain Reaction · RNA, Messenger · Vascular Endothelial Growth Factor A


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-1α-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. © 2007 American Heart Association, Inc.