title: Arteriovenous fistula stenosis in hemodialysis patients is characterized by an increased adventitial fibrosis.
abstract: BACKGROUND
  Arteriovenous fistula (AVF) stenosis is the major cause of vascular access failure in hemodialysis. Adventitial remodeling has been suggested to play a role in the pathogenesis of AVF stenosis. This study aimed to evaluate adventitial fibrosis in stenotic AVF and investigate the underlying molecular mechanisms.
  
  
  METHODS
  Forty-four patients undergoing surgery for AVF creation were examined; ten presented AVF failure, with histological-proven AVF stenosis.
  
  
  RESULTS
  In stenotic AVF we observed a significant increase of adventitia extracellular matrix deposition and alpha-smooth muscle actin (α-SMA)(+) cell numbers; most of these cells were myofibroblast (α-SMA(+)/vimentin(+)). Phosphorylated platelet-derived growth factor β receptor (p-PDGFRβ) was significantly increased within the adventitia of stenotic compared to native AVF, along with a marked increase in the phosphorylation of Akt and ERK, two key kinases in PDGFRβ signalling. Myofibroblasts were the main cell type associated with the activation of p-PDGFRβ. At the same time, we observed a significant adventitial vessels rarefaction in stenotic AVF, as demonstrated by a reduced CD34 expression. This event was associated with a marked reduction in the expression of KDR/fetal liver kinase-1, the main vascular endothelial growth factor receptor. The degree of adventitial fibrosis was directly correlated with the extent of adventitial α-SMA and inversely associated with adventitial CD34 expression. Finally, we observed an increase in CD34(+)/α-SMA(+) cells within the adventitia of failed AVF.
  
  
  CONCLUSIONS
  This study suggests that AVF failure is associated with an increased adventitial fibrosis, myofibroblast activation and capillary rarefaction, potentially linked with endothelial-to-mesenchymal transition. In this scenario, our data suggest that PDGF may play a pathogenic role.
authors.affiliation: Renal, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Simone
authors.forename: Antonia
authors.initials: A
authors.lastname: Loverre
authors.forename: Marica
authors.initials: M
authors.lastname: Cariello
authors.forename: Chiara
authors.initials: C
authors.lastname: Divella
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Castellano
authors.forename: Loreto
authors.initials: L
authors.lastname: Gesualdo
authors.forename: Giovanni
authors.initials: G
authors.lastname: Pertosa
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Grandaliano
mesh_terms: D000328:Adult; D063194:Adventitia / Q000737:chemistry / Q000473:pathology*; D000368:Aged; D001166:Arteriovenous Shunt, Surgical / Q000009:adverse effects*; D015415:Biomarkers / Q000032:analysis; D001706:Biopsy; D003251:Constriction, Pathologic; D042783:Endothelial Cells / Q000737:chemistry / Q000473:pathology; D005260:Female; D005355:Fibrosis; D006083:Graft Occlusion, Vascular / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007676:Kidney Failure, Chronic / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D058628:Myofibroblasts / Q000737:chemistry / Q000378:metabolism; D011446:Prospective Studies; D006435:Renal Dialysis; D015398:Signal Transduction; D017211:Treatment Failure; D066253:Vascular Remodeling; D014680:Veins / Q000737:chemistry / Q000473:pathology*
chemical_list: D015415:Biomarkers