RGD Reference Report - Adventitial transduction of lentivirus-shRNA-VEGF-A in arteriovenous fistula reduces venous stenosis formation. - Rat Genome Database

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Adventitial transduction of lentivirus-shRNA-VEGF-A in arteriovenous fistula reduces venous stenosis formation.

Authors: Yang, Binxia  Janardhanan, Rajiv  Vohra, Pawan  Greene, Eddie L  Bhattacharya, Santanu  Withers, Sarah  Roy, Bhaskar  Nieves Torres, Evelyn C  Mandrekar, Jaywant  Leof, Edward B  Mukhopadhyay, Debabrata  Misra, Sanjay 
Citation: Yang B, etal., Kidney Int. 2014 Feb;85(2):289-306. doi: 10.1038/ki.2013.290. Epub 2013 Aug 7.
RGD ID: 13204800
Pubmed: PMID:23924957   (View Abstract at PubMed)
PMCID: PMC3844094   (View Article at PubMed Central)
DOI: DOI:10.1038/ki.2013.290   (Journal Full-text)

Venous neointimal hyperplasia (VNH) causes hemodialysis vascular access failure. Here we tested whether VNH formation occurs in part due to local vessel hypoxia caused by surgical trauma to the vasa vasorum of the outflow vein at the time of arteriovenous fistula placement. Selective targeting of the adventitia of the outflow vein at the time of fistula creation was performed using a lentivirus-delivered small-hairpin RNA that inhibits VEGF-A expression. This resulted in significant increase in mean lumen vessel area, decreased media/adventitia area, and decreased constrictive remodeling with a significant increase in apoptosis (increase in caspase 3 activity and TUNEL staining) accompanied with decreased cellular proliferation and hypoxia-inducible factor-1α at the outflow vein. There was significant decrease in cells staining positive for α-smooth muscle actin (a myofibroblast marker) and VEGFR-1 expression with a decrease in MMP-2 and MMP-9. These results were confirmed in animals that were treated with humanized monoclonal antibody to VEGF-A with similar results. Since hypoxia can cause fibroblast to differentiate into myofibroblasts, we silenced VEGF-A gene expression in fibroblasts and subjected them to hypoxia. This decreased myofibroblast production, cellular proliferation, cell invasion, MMP-2 activity, and increased caspase 3. Thus, VEGF-A reduction at the time of arteriovenous fistula placement results in increased positive vascular remodeling.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
MMP2HumanArteriovenous Fistula treatmentISOMmp2 (Mus musculus) RGD 
MMP9HumanArteriovenous Fistula treatmentISOMmp9 (Mus musculus) RGD 
Mmp2RatArteriovenous Fistula treatmentISOMmp2 (Mus musculus) RGD 
Mmp2MouseArteriovenous Fistula treatmentIDA  RGD 
Mmp9RatArteriovenous Fistula treatmentISOMmp9 (Mus musculus) RGD 
Mmp9MouseArteriovenous Fistula treatmentIDA  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Mmp2  (matrix metallopeptidase 2)
Mmp9  (matrix metallopeptidase 9)

Genes (Mus musculus)
Mmp2  (matrix metallopeptidase 2)
Mmp9  (matrix metallopeptidase 9)

Genes (Homo sapiens)
MMP2  (matrix metallopeptidase 2)
MMP9  (matrix metallopeptidase 9)


Additional Information