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


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-1alpha-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.
van Weel
Vincent
V
Gaubius Laboratory TNO-Quality of Life, P.O. Box 2215, 2301CE Leiden, The Netherlands.
Seghers
Leonard
L
de Vries
Margreet R
MR
Kuiper
Esther J
EJ
Schlingemann
Reinier O
RO
Bajema
Ingeborg M
IM
Lindeman
Jan H N
JH
Delis-van Diemen
Pien M
PM
van Hinsbergh
Victor W M
VW
van Bockel
J Hajo
JH
Quax
Paul H A
PH
D000208:Acute Disease; D000368:Aged; D000369:Aged, 80 and over; D000671:Amputation, Surgical; D002196:Capillaries / Q000473:pathology; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000032:analysis* / Q000235:genetics; D002908:Chronic Disease; D005121:Extremities / Q000098:blood supply*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007511:Ischemia / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000601:surgery; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000098:blood supply / Q000737:chemistry* / Q000473:pathology / Q000503:physiopathology; D018919:Neovascularization, Physiologic; D016491:Peripheral Vascular Diseases / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D012333:RNA, Messenger / Q000032:analysis; D019718:Receptors, CXCR4 / Q000032:analysis* / Q000235:genetics; D040262:Receptors, Vascular Endothelial Growth Factor / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis* / Q000235:genetics
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D012333:RNA, Messenger; D019718:Receptors, CXCR4; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D040262:Receptors, Vascular Endothelial Growth Factor