Psychogenic stress-induced expression, function and regulation of VEGF receptor signaling pathways in the neural pathways to the urinary bladder

Stress has been implicated in the exacerbation of symptoms associated with functional lower urinary tract disorders, such as interstitial cystitis (IC)/bladder pain syndrome (BPS) in humans. Current research suggests a new, potential role of vascular endothelial growth factor (VEGF) signaling in bladder dysfunction, where VEGF and associated receptors are upregulated in bladder reflex pathways in a preclinical animal model of IC/BPS. Additional research also associates increased VEGF expressions in the dorsal root ganglia (DRG) with pain modulation, following CNS or PNS injury. We have examined psychogenic stress-induced expression, function and regulation of VEGF/receptors in neural circuitry controlling the urinary bladder. A repeated variate stress (RVS) model was used to model psychogenic stress using mice (n=6 each for RVS-exposed and control groups). Quantitative PCR analyses were performed to determine the expression of VEGF, VEGF receptors 1 (VEGFR1) and 2 (VEGFR2), and VEGF co-receptor Neuropilin 2 (Nrp-2) in the bladder, lumbosacral spinal cord (L1, L2, L5, L6, S1) and corresponding DRGs. The results demonstrate that VEGF/receptor transcripts are present in neural pathways controlling urinary bladder function and in the urinary bladder. Regulation of VEGF/receptor transcript expression was observed in the bladder and DRG in males exposed to RVS, and in the spinal cord and DRG in females exposed to RVS; thereby implicating that different parts of the micturition reflex system are more responsive to RVS. The functional role of VEGF/receptor system in the urinary bladder was assessed using administration of a known VEGFR2 antagonist, Ki 8751 in control and RVS-exposed mice during conscious cystometry. No changes were observed to voiding frequency or bladder capacity for both control and RVSexposed mice after receiving Ki 8751. Functional studies suggest Ki 8751 may not be an effective treatment to restore RVS-induced bladder dysfunction. Future studies should consider examining the functional contribution of Nrp-2 in the VEGF/receptor system in bladder reflexes of mice exposed to RVS. The replication of this study is also recommended in mice exposed to prolonged RVS of at least 14 days or more