title: Molecular reactions and ultrastructural damage in the chronically ischemic bladder.
abstract: OBJECTIVE
  Clinical and basic research data suggest that pelvic ischemia may contribute to bladder overactivity. We characterized the molecular and ultrastructural reactions of the chronically ischemic bladder.
  
  
  METHODS
  A model of pelvic ischemia was developed by creating iliohypogastric/pudendal arterial atherosclerosis in rabbits. At 12 weeks conscious urinary frequency was examined, bladder blood flow was recorded and cystometrograms were done using general anesthesia. Bladder tissue was processed for molecular and ultrastructural analysis using quantitative real-time polymerase chain reaction, Western blot and transmission electron microscopy.
  
  
  RESULTS
  Conscious urinary frequency and the frequency of spontaneous bladder contractions significantly increased in animals with pelvic ischemia. Bladder ischemia up-regulated the gene and protein expression of hypoxia inducible factor-1α, transforming growth factor-β and nerve growth factor B. Vascular endothelial growth factor gene expression also increased but protein levels were unchanged. Transmission electron microscopy of ischemic bladder samples showed swollen mitochondria with degraded granules, thickened epithelium, deformed muscle fascicles, collagen deposition and impaired microvasculature with thickened intima and disrupted endothelial cell junctions. Degenerating axonal and Schwann cell profiles, and myelin sheath splitting around axons and Schwann cells were evident in ischemic bladders.
  
  
  CONCLUSIONS
  Interrupting pelvic blood flow resulted in an ischemic overactive bladder and significant increase in conscious urinary frequency. Molecular responses involving hypoxia inducible factor, transforming growth factor-β, vascular endothelial growth factor and nerve growth factor were associated with mitochondrial injury, fibrosis, microvasculature damage and neurodegeneration. Ischemia may have a key role in bladder overactivity and lower urinary tract symptoms.
authors.affiliation: Department of Pathology, Veterans Affairs Boston Healthcare System, Boston, Massachusetts, USA. kazadzoi@bu.edu
authors.forename: Kazem M
authors.initials: KM
authors.lastname: Azadzoi
authors.forename: Bin-Guan
authors.initials: BG
authors.lastname: Chen
authors.forename: Ziv M
authors.initials: ZM
authors.lastname: Radisavljevic
authors.forename: Mike B
authors.initials: MB
authors.lastname: Siroky
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D004848:Epithelium / Q000648:ultrastructure; D005786:Gene Expression Regulation / Q000502:physiology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007150:Immunohistochemistry; D059411:Lower Urinary Tract Symptoms / Q000503:physiopathology; D008297:Male; D046529:Microscopy, Electron, Transmission; D055806:Microvessels / Q000378:metabolism / Q000648:ultrastructure; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000648:ultrastructure; D020932:Nerve Growth Factor / Q000378:metabolism; D011817:Rabbits; D060888:Real-Time Polymerase Chain Reaction; D012039:Regional Blood Flow; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology; D001743:Urinary Bladder / Q000098:blood supply* / Q000503:physiopathology / Q000648:ultrastructure*; D053201:Urinary Bladder, Overactive / Q000503:physiopathology*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016212:Transforming Growth Factor beta; D020932:Nerve Growth Factor