Document Detail


Adenoviral gene transfer with soluble vascular endothelial growth factor receptors impairs angiogenesis and perfusion in a murine model of hindlimb ischemia.
MedLine Citation:
PMID:  15477417     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: The purpose of the current study was to examine the contribution of endogenous vascular endothelial growth factor (VEGF) to ischemia-induced angiogenesis and perfusion. METHODS AND RESULTS: C57BL/6J mice (n=28) were subjected to unilateral hindlimb ischemia after intravenous injection of recombinant adenoviruses (10(9) plaque-forming units) encoding the ligand-binding ectodomain of VEGF receptor 1 (VEGFR1/Ad Flt1), VEGF receptor 2 (VEGFR2/Ad Flk1-Fc), a control murine IgG2alpha Fc fragment (Ad Fc), or vehicle (phosphate-buffered saline). Hindlimb perfusion was assessed by both laser Doppler and fluorescent microsphere injection 10 days after surgery. The role of endogenous VEGF in ischemia-induced angiogenesis and arteriogenesis was measured by capillary density and microangiography, respectively. Adenoviral gene transfer with soluble VEGFRs significantly attenuated hindlimb perfusion as assessed by laser Doppler and microsphere analysis (P<0.05). Furthermore, soluble VEGFRs significantly reduced ischemia-induced angiogenesis and collateral growth and inhibited histological recovery of muscle tissue. Adverse events consistent with ongoing vascular insufficiency such as limb necrosis or gangrene were observed only in animals expressing soluble VEGFRs and not in control animals. CONCLUSIONS: Systemic, soluble receptor-mediated VEGF inhibition indicates an essential role for endogenous VEGF during postischemic angiogenesis and hindlimb perfusion.
Authors:
Johannes Jacobi; Betty Y Y Tam; Grace Wu; Jana Hoffman; John P Cooke; Calvin J Kuo
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.     Date:  2004-10-11
Journal Detail:
Title:  Circulation     Volume:  110     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2004 Oct 
Date Detail:
Created Date:  2004-10-19     Completed Date:  2005-07-06     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2424-9     Citation Subset:  AIM; IM    
Affiliation:
Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, Calif 94305-5156, USA.
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MeSH Terms
Descriptor/Qualifier:
Adenoviridae / genetics*
Animals
Collateral Circulation*
Gangrene
Genetic Vectors* / adverse effects*
Hindlimb / blood supply*,  pathology
Immunoglobulin Fc Fragments / genetics,  physiology
Ischemia / physiopathology*
Laser-Doppler Flowmetry
Male
Mice
Mice, Inbred C57BL
Microspheres
Necrosis
Neovascularization, Physiologic
Peptide Fragments / genetics,  physiology
Protein Structure, Tertiary
Recombinant Fusion Proteins / physiology
Solubility
Vascular Endothelial Growth Factor A / physiology
Vascular Endothelial Growth Factor Receptor-1 / genetics,  physiology*
Vascular Endothelial Growth Factor Receptor-2 / genetics,  physiology*
Grant Support
ID/Acronym/Agency:
1 R01 CA95654-01/CA/NCI NIH HHS; P01AI50153/AI/NIAID NIH HHS; R01 HL-63685/HL/NHLBI NIH HHS; R01 HL-75774/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Immunoglobulin Fc Fragments; 0/Peptide Fragments; 0/Recombinant Fusion Proteins; 0/Vascular Endothelial Growth Factor A; EC 2.7.10.1/Vascular Endothelial Growth Factor Receptor-1; EC 2.7.10.1/Vascular Endothelial Growth Factor Receptor-2

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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