VEGF signaling mediates bladder neuroplasticity and inflammation in response to BCG

Abstract

BackgroundThis work tests the hypothesis that increased levels of vascular endothelial growth factor (VEGF) observed during bladder inflammation modulates nerve plasticity.MethodsChronic inflammation was induced by intravesical instillations of Bacillus Calmette-Guérin (BCG) into the urinary bladder and the density of nerves expressing the transient receptor potential vanilloid subfamily 1 (TRPV1) or pan-neuronal marker PGP9.5 was used to quantify alterations in peripheral nerve plasticity. Some mice were treated with B20, a VEGF neutralizing antibody to reduce the participation of VEGF. Additional mice were treated systemically with antibodies engineered to specifically block the binding of VEGF to NRP1 (anti-NRP1B) and NRP2 (NRP2B), or the binding of semaphorins to NRP1 (anti-NRP1 A) to diminish activity of axon guidance molecules such as neuropilins (NRPs) and semaphorins (SEMAs). To confirm that VEGF is capable of inducing inflammation and neuronal plasticity, another group of mice was instilled with recombinant VEGF165 or VEGF121 into the urinary bladder.ResultsThe major finding of this work was that chronic BCG instillation resulted in inflammation and an overwhelming increase in both PGP9.5 and TRPV1 immunoreactivity, primarily in the sub-urothelium of the urinary bladder. Treatment of mice with anti-VEGF neutralizing antibody (B20) abolished the effect of BCG on inflammation and nerve density.NRP1A and NRP1B antibodies, known to reduce BCG-induced inflammation, failed to block BCG-induced increase in nerve fibers. However, the NRP2B antibody dramatically potentiated the effects of BCG in increasing PGP9.5-, TRPV1-, substance P (SP)-, and calcitonin gene-related peptide (CGRP)-immunoreactivity (IR). Finally, instillation of VEGF121 or VEGF165 into the mouse bladder recapitulated the effects of BCG and resulted in a significant inflammation and increase in nerve density.ConclusionsFor the first time, evidence is being presented supporting that chronic BCG instillation into the mouse bladder promotes a significant increase in peripheral nerve density that was mimicked by VEGF instillation. Effects of BCG were abolished by pre-treatment with neutralizing VEGF antibody. The present results implicate the VEGF pathway as a key modulator of inflammation and nerve plasticity, introduces a new animal model for investigation of VEGF-induced nerve plasticity, and suggests putative mechanisms underlying this phenomenon.

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

“…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).…”

Down Regulation of Vascular Endothelial Growth Factor Is Associated With Decreased Inflammation After Intravesical OnabotulinumtoxinA Injections Combined With Hydrodistention for Patients With Interstitial Cystitis—Clinical Results and Immunohistochemistry Analysis

“…In addition, in mouse bladder inflammation induced by BCG (bacille Calmette-Gu erin) instillation, a significant increase in peripheral nerve density and protein gene product 9.5 can be abolished by pretreatment with anti-VEGF neutralizing antibody. 16 The VEGF pathway is likely to mediate bladder neuroplasticity and inflammation in response to BCG.…”

Role of Vascular Endothelial Growth Factor in the Pathogenesis of Atopic Dermatitis in Children

“…Сред-няя оценка по международной системе SCORAD со-ставила (41,46 ± 26,42) балла. Большинство детей имели сопутствующие аллергические заболевания: аллерги-ческий ринит -73,33 %, бронхиальную астму -13,33 %, острая крапивница зарегистрирована в анамнезе у 3 больных (10 % [5,7,8]. Причем кон-центрация данного цитокина коррелирует со степенью тяжести заболевания (r = 0,49).…”

“…Так, у пациентов с ограниченной фор-мой его величина равна (113,08 ± 29,23) пг/мл, тогда как при распространенном и диффузном процессах зна-чения гораздо выше [(319,32 ± 32) пг/мл и (812,60 ± 221,40) пг/мл]. Возможно, это связано с тем, что VEGF не только оказывает влияние на развития кровеносных сосудов кожи, но и является аутокринным регулятором гиперплазии эпидермиса [8], что проявляется в виде обширных очагов лихенификации у обследованных нами пациентов.…”