Anti‐vascular endothelial growth factor treatment decreases bladder pain in cyclophosphamide cystitis: a Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network animal model study

Abstract

Objective To investigate whether treatment with anti-VEGF (vascular endothelial growth factor) neutralizing antibodies can reduce pain and voiding dysfunction in the cyclophosphamide (CYP) cystitis model of bladder pain in mice. Materials and Methods Adult female mice received anti-VEGF neutralizing antibodies (10 mg/kg intraperitoneal B20-4.1.1 VEGF mAb) or saline (control) pre-treatment, followed by CYP (150 mg/kg intraperitoneal) to induce acute cystitis. Pelvic nociceptive responses were assessed by applying von Frey filaments to the pelvic area. Spontaneous micturition was assessed using the void spot assay. Results Systemic anti-VEGF neutralizing antibodies treatment significantly reduced the pelvic nociceptive response to CYP cystitis compared to control (saline). In the anti-VEGF pre-treatment group, there was a significant increase in pelvic hypersensitivity measured by the area under the curve (AUC) with von Frey filaments at 5 hours post-CYP (p=0.0035). However by 48 and 96 hours post-CYP, the pelvic hypersensitivity have reduced by 54% and 47% respectively compared to the 5 hours post-CYP time point, and were no longer significantly different from the baseline (p=0.22 and 0.17 respectively). There was no difference in urinary frequency and mean voided volume between the two pre-treatment groups. Conclusion Systemic blockade of VEGF signaling with anti-VEGF neutralizing antibodies was effective in reducing pelvic/bladder pain in the CYP cystitis model of bladder pain. Our data support the further investigation of the use of anti-VEGF antibodies to manage bladder pain or visceral pain.

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

“…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 . Furthermore, it has recently been reported that VEGF was thought to be one of the crucial urine markers to discriminate IC/BPS patients from OAB patients, and that urinary symptom and pain severity was significantly correlated with urinary VEGF levels in female IC/BPS patients .…”

“…14 In addition, systemic anti-VEGF neutralizing antibody pretreatment significantly reduced the pelvic nociceptive response to cyclophosphamide-induced cystitis compared with controls in rats. 15 Furthermore, it has recently been reported that VEGF was thought to be one of the crucial urine markers to discriminate IC/BPS patients from OAB patients, 8 and that urinary symptom and pain severity was significantly correlated with urinary VEGF levels in female IC/BPS patients. 16 Taken together, these findings suggest that the increased VEGF levels in bladder tissues or urine, which could be correlated with angiogenesis, may provide new insights into the pathophysiological basis of IC/BPS.…”

Painful Understanding of VEGF

“…Anti-VEGF drugs are also used to attenuate neovascularisation in age-related macular degeneration and diabetic macular oedema (Ferrara, 2004 ; Kim and D'Amore, 2012 ). However, in recent years, the role of the VEGF family in neuroprotection and nociception has received increased attention (Beazley-Long et al, 2013 , 2018 ; Hulse et al, 2014 , 2015 , 2016 ; Selvaraj et al, 2015 ; Hulse, 2017 ; Lai et al, 2017 ). The involvement of VEGF in the pathophysiology of pain is not fully understood, however, the association between this growth factor and some of the main hallmarks of painful diseases warrants the investigation of VEGF as a therapeutic target for pain treatment.…”

A prostate derived commensal Staphylococcus epidermidis strain prevents and ameliorates induction of chronic prostatitis by UPEC infection

“…Notably absent from these increased analytes were cytokines such as IFNg, IL12b (P40 and P70), implicated in another model of CP/CPPS 30 , and IL17. VEGF expression was also shown to be increased in the NPI prophylactic group compared to either CP1 alone or NPI alone, which is interesting given that studies have shown that blockade of VEGF by an antibody reduced pelvic nociceptive responses in cyclophosphamide (CYP) cystitis 31 .…”