Expression of vascular endothelial growth factor, stromal cell-derived factor-1, and CXCR4 in human limb muscle with acute and chronic ischemia
article
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.
Topics
Biomedical ResearchAngiogenesisIschemiaPeripheral artery diseaseSDF-1VEGFchemokine receptor CXCR4hypoxia inducible factor 1alphastromal cell derived factor 1vasculotropin Aacute diseaseadultagedangiogenesisartery diseasearticleblood vesselcapillarychronic diseasecontrolled studycorrelation analysisdown regulationfemalegene controlgene expressionhumanhuman tissueleg amputationleg ischemialeg musclelimb ischemiamalemuscle cellmuscle ischemiapriority journalprotein expressionprotein functionprotein inductionupregulationvascular endotheliumAcute DiseaseAgedAged, 80 and overAmputationCapillariesChemokines, CXCChronic DiseaseExtremitiesFemaleHumansImmunohistochemistryIschemiaMaleMiddle AgedMuscle, SkeletalNeovascularization, PhysiologicPeripheral Vascular DiseasesReceptors, CXCR4Receptors, Vascular Endothelial Growth FactorReverse Transcriptase Polymerase Chain ReactionRNA, MessengerVascular Endothelial Growth Factor A
TNO Identifier
239989
ISSN
10795642
Source
Arteriosclerosis, Thrombosis, and Vascular Biology, 27(6), pp. 1426-1432.
Pages
1426-1432
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