title: Acute stress and intravesical corticotropin-releasing hormone induces mast cell dependent vascular endothelial growth factor release from mouse bladder explants.
abstract: OBJECTIVE
  Corticotropin-releasing hormone is typically released from the hypothalamus but it has proinflammatory effects outside of the brain, possibly through the activation of mast cells. These cells express corticotropin-releasing hormone receptors with selective secretion of vascular endothelial growth factor, which may be involved in the pathogenesis of painful bladder syndrome/interstitial cystitis. This condition is characterized by bladder inflammation and worsened by stress. We investigated the effect of intravesical corticotropin-releasing hormone and acute restraint stress on vascular endothelial growth factor release from mouse bladder explants and the role of mast cells.
  
  
  METHODS
  The bladder of C57BL/6 mast cell deficient (W/W(v)) and normal congenic (+/+) female mice (Jackson Laboratories, Bar Harbor, Maine) at ages 10 to 12 weeks was catheterized using anesthesia. After emptying urine 1) normal saline or corticotropin-releasing hormone was introduced for 45 minutes, urine was collected and the mice were allowed to recover for 4 hours before sacrifice or 2) the mice were stressed by placing them in a restrainer for 4 hours before sacrifice and urine was collected 2 hours after stress. The bladder was removed 4 hours after stress and processed for corticotropin-releasing hormone immunohistochemical staining. In other experiments the bladder was removed, minced into 1 mm(2) pieces and cultured with or without corticotropin-releasing hormone overnight. Urine and medium were frozen for histamine, interleukin-6, tumor necrosis factor-alpha and vascular endothelial growth factor assay.
  
  
  RESULTS
  Corticotropin-releasing hormone (100 nM) or acute restraint stress (4 hours) increased histamine release in urine and vascular endothelial growth factor release in medium without increasing interleukin-6 or tumor necrosis factor-alpha in the bladder explants of C57BL/6 or +/+ but not W/W(v) mice. No vascular endothelial growth factor, interleukin-6 or tumor necrosis factor-alpha was detected in urine before or after stimulation. Corticotropin-releasing hormone immunoreactivity was present in control bladders but it increased dramatically in the bladder of stressed mice.
  
  
  CONCLUSIONS
  Intravesical corticotropin-releasing hormone and acute restraint stress induced mast cell dependent vascular endothelial growth factor release from bladder explants. These findings suggest that stress, corticotropin-releasing hormone, mast cells and vascular endothelial growth factor might participate in the pathogenesis of painful bladder syndrome/interstitial cystitis, which is worsened by stress, and provide for new therapeutic targets.
authors.affiliation: Department of Biochemistry, Tufts University School of Medicine, Tufts-New England Medical Center, 136 Harrison Avenue, Boston, MA 02111, USA.
authors.forename: J
authors.initials: J
authors.lastname: Cao
authors.forename: W
authors.initials: W
authors.lastname: Boucher
authors.forename: D
authors.initials: D
authors.lastname: Kempuraj
authors.forename: J M
authors.initials: JM
authors.lastname: Donelan
authors.forename: T C
authors.initials: TC
authors.lastname: Theoharides
mesh_terms: D000208:Acute Disease; D000283:Administration, Intravesical; D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000008:administration & dosage / Q000502:physiology*; D008407:Mast Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D013312:Stress, Physiological / Q000276:immunology*; D001743:Urinary Bladder / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D042461:Vascular Endothelial Growth Factor A; D003346:Corticotropin-Releasing Hormone