title: Hypoxia-induced mediators of stem/progenitor cell trafficking are increased in children with hemangioma.
abstract: OBJECTIVE
  The mechanism of neovascularization during the proliferative phase of infantile hemangioma is poorly understood. It is known that circulating bone marrow-derived endothelial progenitor cells (EPCs) form new blood vessels in ischemic tissues using mediators regulated by the transcription factor, HIF-1alpha. Mobilization of EPCs is enhanced by VEGF-A, matrix metalloproteinase (MMP)-9, and estrogen, whereas homing is secondary to localized expression of stromal cell-derived factor-1alpha (SDF-1alpha). We examined whether these mediators of EPC trafficking are upregulated during the proliferation of infantile hemangioma.
  
  
  RESULTS
  Surgical specimens and blood samples were obtained from children with proliferating hemangioma and age-matched controls (n=10, each group). VEGF-A and MMP-9 levels were measured in blood, and tissue sections were analyzed for SDF-1alpha, MMP-9, VEGF-A, and HIF-1alpha. The role of estrogen as a modulator of hemangioma endothelial cell growth was also investigated. We found that all these mediators of EPC trafficking are elevated in blood and specimens from children with proliferating infantile hemangioma. In vitro, the combination of hypoxia and estrogen demonstrated a synergistic effect on hemangioma endothelial cell proliferation.
  
  
  CONCLUSIONS
  These findings demonstrate that proliferating hemangiomas express known mediators of vasculogenesis and suggest that this process may play a role in the initiation or progression of this disease.
authors.affiliation: Stanford University, Department of Surgery, PSRL, GK-201, 257 Campus Drive West, Stanford, CA, 94305-5148, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Kleinman
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Greives
authors.forename: Samara S
authors.initials: SS
authors.lastname: Churgin
authors.forename: Keith M
authors.initials: KM
authors.lastname: Blechman
authors.forename: Eric I
authors.initials: EI
authors.lastname: Chang
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Ceradini
authors.forename: Oren M
authors.initials: OM
authors.lastname: Tepper
authors.forename: Geoffrey C
authors.initials: GC
authors.lastname: Gurtner
mesh_terms: D042501:Angiogenic Proteins / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D015687:Cell Hypoxia; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism; D002675:Child, Preschool; D042783:Endothelial Cells / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D004967:Estrogens / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006391:Hemangioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007223:Infant; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D013234:Stem Cells / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000378:metabolism
chemical_list: D042501:Angiogenic Proteins; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D004967:Estrogens; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D011960:Receptors, Estrogen; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D020780:Matrix Metalloproteinase 9