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

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.

Effects of CYP-Induced Cystitis on Growth Factors and Associated Receptor Expression in Micturition Pathways in Mice with Chronic Overexpression of NGF in Urothelium

“…Other roles for VEGF-VEGF receptor system in the lower urinary tract may involve inflammation-induced lymphangiogenesis and angiogenesis (Saban et al, 2010; Saban, 2015). The present studies demonstrating increased VEGF transcript expression in the urothelium and detrusor of WT and NGF-OE mice with CYP-induced cystitis are consistent with previous studies demonstrating contributions from the VEGF-VEGF receptor system in the structure and function of the lower urinary tract (Cheppudira et al, 2008; Malykhina et al, 2012; Saban et al, 2008a; Saban et al, 2011; Saban et al, 2010; Saban, 2015; Saban et al, 2008b). …”

“…Previous studies have demonstrated that animal models of urinary bladder inflammation and BPS/IC regulate the VEGF-VEGF receptor system in the urothelium (Cheppudira et al, 2008; Malykhina et al, 2012; Saban et al, 2008a; Saban et al, 2011; Saban et al, 2010; Saban, 2015; Saban et al, 2008b). Increased expression of VEGF and receptors has been reported in bladder biopsies from women with BPS/IC and expression of VEGF correlates with pain described by patients (Saban, 2015).…”

“…In CYP-induced cystitis, the VEGF-VEGF receptor system is increased in the urothelium and chronic urothelial overexpression of NGF increases VEGF receptor and protein expression in the urothelium and detrusor smooth muscle (Cheppudira et al, 2008). Intravesical instillation of VEGF produced bladder inflammation, increased voiding frequency, increased abdominal sensitivity and increased bladder nerve density in specific nerve populations including TRPV1-, substance P-, and calcitonin gene-related peptide-immunoreactive nerve fibers (Malykhina et al, 2012; Saban et al, 2011). Other roles for VEGF-VEGF receptor system in the lower urinary tract may involve inflammation-induced lymphangiogenesis and angiogenesis (Saban et al, 2010; Saban, 2015).…”

Angiogenesis in bladder tissues is strongly correlated with urinary frequency and bladder pain in patients with interstitial cystitis/bladder pain syndrome

“…The significant increased expression of VEGF in bladder biopsied tissues has been reported in IC/BPS patients compared with controls, which was associated with the degree of pain . The basic research findings have shown that intravesical instillation of VEGF modulated sensory and motor nerve plasticity, and, consequently, bladder function and visceral sensitivity in rats . In addition, systemic anti‐VEGF neutralizing antibody pretreatment significantly reduced the pelvic nociceptive response to cyclophosphamide‐induced cystitis compared with controls in rats .…”

Targeting VEGF and Its Receptors for the Treatment of Osteoarthritis and Associated Pain

“…NGF induces VEGF expression in sensory neurons in the dorsal root ganglion (DRG), suggesting further cross‐talk between sensory neurons and blood vessels. Exogenous, intravesicular VEGF administration increased peripheral nerve density and pain . The influence of VEGF on pain may occur indirectly from VEGF stimulation of angiogenesis and sensory neuron ingrowth or inflammation.…”