VEGF induces sensory and motor peripheral plasticity, alters bladder function, and promotes visceral sensitivity

Anna P Malykhina,Ricardo Saban,Miles L Epstein,Qi Lei,Chris S Erickson,Marcia R Saban,Carole A Davis

doi:10.1186/1472-6793-12-15

Abstract

BackgroundThis 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.ResultsIn 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.ConclusionsFor 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.

Highlights

This work tests the hypothesis that bladder instillation with vascular endothelial growth factor (VEGF) modulates sensory and motor nerve plasticity, and, bladder function and visceral sensitivity
This finding led to a new appreciation of the role of VEGF in neuronal development [14,18] and stimulated us to review a possible link between VEGF-induced inflammation and bladder nerve plasticity
Similar results were obtained with choline acetyltransferase (ChAT) mice indicating that 1 and 2 weekly VEGF instillations provoked similar increases in transient receptor potential vanilloid subfamily 1 (TRPV1) immune reactivity

Summary

Introduction

This work tests the hypothesis that bladder instillation with vascular endothelial growth factor (VEGF) modulates sensory and motor nerve plasticity, and, bladder function and visceral sensitivity. Several mediators and their respective receptors have been proposed to modulate peripheral nerve plasticity in the LUT, including but not limited to: purinergic receptors in general [2] or P2X receptor in particular [3], TRPV1 [1,4], substance P acting on NK1 receptors [5], protease activated receptors [6], and nerve growth factor and its receptors [7] In this context, the development of cross-sensitization in the pelvis is one of the suggested mechanisms underlying co-morbidity of pelvic disorders which is frequently observed in the clinical setting [8]. Colonic inflammation-induced activation of TRPV1 receptors at the peripheral sensory terminals results in an up-regulation of voltage gated Na+ channels on the cell soma of bladder sensory neurons [9] This increase in channels may underlie the occurrence of peripheral cross-sensitization in the pelvis and functional chronic pelvic pain [9]

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