title: VEGF induces sensory and motor peripheral plasticity, alters bladder function, and promotes visceral sensitivity.
abstract: BACKGROUND
  This work tests the hypothesis that bladder instillation with vascular endothelial growth factor (VEGF) modulates sensory and motor nerve plasticity, and, consequently, bladder function and visceral sensitivity.In addition to C57BL/6J, ChAT-cre mice were used for visualization of bladder cholinergic nerves. The direct effect of VEGF on the density of sensory nerves expressing the transient receptor potential vanilloid subfamily 1 (TRPV1) and cholinergic nerves (ChAT) was studied one week after one or two intravesical instillations of the growth factor.To study the effects of VEGF on bladder function, mice were intravesically instilled with VEGF and urodynamic evaluation was assessed. VEGF-induced alteration in bladder dorsal root ganglion (DRG) neurons was performed on retrogradly labeled urinary bladder afferents by patch-clamp recording of voltage gated Na+ currents. Determination of VEGF-induced changes in sensitivity to abdominal mechanostimulation was performed by application of von Frey filaments.
  
  
  RESULTS
  In addition to an overwhelming increase in TRPV1 immunoreactivity, VEGF instillation resulted in an increase in ChAT-directed expression of a fluorescent protein in several layers of the urinary bladder. Intravesical VEGF caused a profound change in the function of the urinary bladder: acute VEGF (1 week post VEGF treatment) reduced micturition pressure and longer treatment (2 weeks post-VEGF instillation) caused a substantial reduction in inter-micturition interval. In addition, intravesical VEGF resulted in an up-regulation of voltage gated Na(+) channels (VGSC) in bladder DRG neurons and enhanced abdominal sensitivity to mechanical stimulation.
  
  
  CONCLUSIONS
  For the first time, evidence is presented indicating that VEGF instillation into the mouse bladder promotes a significant increase in peripheral nerve density together with alterations in bladder function and visceral sensitivity. The VEGF pathway is being proposed as a key modulator of neural plasticity in the pelvis and enhanced VEGF content may be associated with visceral hyperalgesia, abdominal discomfort, and/or pelvic pain.
authors.affiliation: Department of Surgery, Division of Urology, University of Pennsylvania School of Medicine, Glenolden, 19036-2307, USA.
authors.forename: Anna P
authors.initials: AP
authors.lastname: Malykhina
authors.forename: Qi
authors.initials: Q
authors.lastname: Lei
authors.forename: Chris S
authors.initials: CS
authors.lastname: Erickson
authors.forename: Miles L
authors.initials: ML
authors.lastname: Epstein
authors.forename: Marcia R
authors.initials: MR
authors.lastname: Saban
authors.forename: Carole A
authors.initials: CA
authors.lastname: Davis
authors.forename: Ricardo
authors.initials: R
authors.lastname: Saban
mesh_terms: D000283:Administration, Intravesical; D000818:Animals; D059329:Cholinergic Neurons / Q000378:metabolism / Q000502:physiology; D005260:Female; D005727:Ganglia, Spinal / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009046:Motor Neurons / Q000378:metabolism / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology*; D010525:Peripheral Nerves / Q000378:metabolism / Q000502:physiology*; D011984:Sensory Receptor Cells / Q000378:metabolism / Q000502:physiology*; D050916:TRPV Cation Channels / Q000378:metabolism; D001743:Urinary Bladder / Q000294:innervation / Q000378:metabolism / Q000502:physiology*; D014554:Urination / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D014781:Viscera / Q000294:innervation / Q000378:metabolism / Q000502:physiology*; D061566:Voltage-Gated Sodium Channels / Q000378:metabolism
chemical_list: D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D042461:Vascular Endothelial Growth Factor A; D061566:Voltage-Gated Sodium Channels; C467480:vascular endothelial growth factor A, mouse