Urothelial expression of neuropilins and VEGF receptors in control and interstitial cystitis patients

Abstract

Interstitial cystitis (IC) is a chronic and painful bladder syndrome of unknown cause with no reliable biological marker or effective therapy. Vascular endothelial growth factor (VEGF), which plays a key role in bladder inflammation, is closely associated with the vascular alterations observed in patients with IC. However, our recent findings of VEGF receptors (VEGF-Rs) and VEGF coreceptors on nonendothelial cells in human and mouse urothelium suggest that additional VEGF targets and functions are possible in IC bladders. We report here that VEGF-Rs and coreceptors (neuropilins; NRP) are strongly expressed in both the human bladder urothelium and in the human bladder cancer cell line (J82) and that the expression of NRP2 and VEGF-R1 is significantly downregulated in IC compared with control subjects. In addition, treatment of J82 cells with bacillus Calmette-Guérin (BCG), a novel treatment strategy for IC, upregulates the messages for NRPs and VEGF-Rs. Furthermore, intravesical instillation of an internalizable VEGF fluorescent tracer (scVEGF/Cy5.5) into mouse urinary bladders results in a marked ligand accumulation in the urothelium and bladder parenchyma, indicating that urothelial VEGF-Rs are functionally active and capable of ligand interaction and internalization. Our results suggest that the VEGF pathway is altered in IC, that urinary VEGF may gain access to the bladder wall via these receptors, and that BCG treatment may replenish the missing VEGF-Rs/NRP receptors. Together, these results suggest that levels of NRPs, VEGF-Rs, and VEGF are new putative markers for the diagnosis of IC and that modulating these receptors can be exploited as therapeutic strategies.

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).…”

Cell biology and physiology of the uroepithelium

“…9). The uroepithelium detects these sensory stimuli by expressing a large number of surface receptors and ion channels, including EGF family ErbB1-3 receptors (15,209), A 1 , A 2a , A 2b , and A 3 receptors (235), ␣-and ␤-adrenergic receptors (20,26), bradykinin receptors (41), cannabinoid receptors (74,220), fractalkine receptor (236), neurokinin receptor (49), nicotinic and muscarinic receptors (M 1 -M 5 ) (18,22,40,77,121), purinergic P2X 1 , P2X 2 , P2X 3 , P2X 4 , P2X 5 , P2X 6 , P2X 7 , P2Y 1, P2Y 2 , and P2Y 4 receptors (27,58,129,197,200,218,225), protease-activated receptors (47), VEGF receptor/neuropilins (39,176), acid-sensitive ion channels (14,122), ENaC (61,134,224), the NSCC (223,234), TRAAK (234), TREK-1 (234), and the TRP family channels TRPV1, TRPV2, TRPV4, and TRPM8 (21,22,25,33,193) (Fig. 9).…”

Potential urine and serum biomarkers for patients with bladder pain syndrome/interstitial cystitis

“…Several important proteins associated with bladder inflammation were also investigated as biomarkers for the diagnosis of BPS/IC. Additionally, glomerulations during cystoscopic hydrodistention is highly associated with overexpression of angiogenic growth factors, such as platelet-derived endothelial cell growth factor/thymidine phosphorylase, 65 vascular endothelial growth factor 66 and hypoxia-inducible factor-1-alpha. 67 Measuring the urine concentrations of these angiogenic growth factors could be a new and useful method for the diagnosis of BPS/IC.…”