Overexpression of NGF in mouse urothelium leads to neuronal hyperinnervation, pelvic sensitivity, and changes in urinary bladder function

Abstract

Schnegelsberg B, Sun T, Cain G, Bhattacharya A, Nunn PA, Ford AP, Vizzard MA, Cockayne DA. Overexpression of NGF in mouse urothelium leads to neuronal hyperinnervation, pelvic sensitivity, and changes in urinary bladder function. Am J Physiol Regul Integr Comp Physiol 298: R534 -R547, 2010. First published December 23, 2009; doi:10.1152/ajpregu.00367.2009.-NGF has been suggested to play a role in urinary bladder dysfunction by mediating inflammation, as well as morphological and functional changes, in sensory and sympathetic neurons innervating the urinary bladder. To further explore the role of NGF in bladder sensory function, we generated a transgenic mouse model of chronic NGF overexpression in the bladder using the urothelium-specific uroplakin II (UPII) promoter. NGF mRNA and protein were expressed at higher levels in the bladders of NGF-overexpressing (NGF-OE) transgenic mice compared with wild-type littermate controls from postnatal day 7 through 12-16 wk of age. Overexpression of NGF led to urinary bladder enlargement characterized by marked nerve fiber hyperplasia in the submucosa and detrusor smooth muscle and elevated numbers of tissue mast cells. There was a marked increase in the density of CGRP-and substance P-positive C-fiber sensory afferents, neurofilament 200-positive myelinated sensory afferents, and tyrosine hydroxylase-positive sympathetic nerve fibers in the suburothelial nerve plexus. CGRP-positive ganglia were also present in the urinary bladders of transgenic mice. Transgenic mice had reduced urinary bladder capacity and an increase in the number and amplitude of nonvoiding bladder contractions under baseline conditions in conscious open-voiding cystometry. These changes in urinary bladder function were further associated with an increased referred somatic pelvic hypersensitivity. Thus, chronic urothelial NGF overexpression in transgenic mice leads to neuronal proliferation, focal increases in urinary bladder mast cells, increased urinary bladder reflex activity, and pelvic hypersensitivity. NGF-overexpressing mice may, therefore, provide a useful transgenic model for exploring the role of NGF in urinary bladder dysfunction. nerve growth factor; urothelium; transgenic mouse; bladder hypersensitivity; inflammation; afferent innervation NGF IS A POTENT NEUROTROPHIN that exerts pleiotropic effects in the peripheral and central nervous system. It regulates sensory and sympathetic neuronal development and maintenance (41) and plays a role in painful somatic and visceral inflammation (3,15,32,70,84,85). The effects of NGF are mediated through the TrkA and p75 NTR receptors and are tissue specific. It is well documented that NGF plays an important role in inflammation of the urinary bladder, colon, and lung (21,31,93,100). Although the contribution of NGF to urinary bladder function is unclear, it seems to play a role in urinary bladder hyperreflexia or overactivity (15,16,23,34,40,78,111). NGF administered intrathecally (107), intravesically (23), intramuscularly to the detrusor smooth muscle ...

Urothelial Signaling

“…Thus various stimuli can lead to secretion of chemical substances capable of modulating the activity of underlying smooth muscle (141,271), as well as nearby sensory neurons. For example, urothelial-specific overexpression of nerve growth factor (NGF) results in increased bladder nerve "sprouting" and increased voiding frequency (119,251). It has been shown that urothelial-derived NO can be released in response to mechanical as well as chemical stimulation and may either facilitate or inhibit the activity of bladder afferent nerves conveying bladder sensation (18,42).…”

Inflammation in CRPS: Role of the sympathetic supply

“…CRPS pain not only is influenced by peripheral autonomic changes but also by central changes Postganglionic sympathetic neurons might modulate inflammatory reactions, either directly by releasing prostaglandins (Gonzales et al, 1991) or indirectly by releasing NGF from vascular smooth muscle cells (Tuttle et al, 1993) or the bladder (Schnegelsberg et al, 2010). As noted above, the sympathetic nervous system influences innate immunity via dendritic cells, which are modulated by adrenoreceptors: α 1 -adrenoceptors stimulate and β 2 -adrenoceptors inhibit dendritic cell migration and immune system activation (Maestroni, 2006).…”

Repeated variate stress in male rats induces increased voiding frequency, somatic sensitivity, and urinary bladder nerve growth factor expression

“…Neurotrophins, particularly NGF, are thought to play a role in bladder function (18,20,24,25,29,34,77), and particularly in bladder diseases including IC/BPS (44,50), OAB (37,42) and bladder outlet obstruction (43). NGF exerts pleiotropic effects in the peripheral and central nervous system, regulating sensory and sympathetic neuronal development and maintenance (25,48,61). NGF plays wellestablished roles in urinary bladder inflammation (61,71), most likely contributing to increased voiding frequency (18,20,24,28,33,49,77).…”

“…NGF exerts pleiotropic effects in the peripheral and central nervous system, regulating sensory and sympathetic neuronal development and maintenance (25,48,61). NGF plays wellestablished roles in urinary bladder inflammation (61,71), most likely contributing to increased voiding frequency (18,20,24,28,33,49,77). Administration of NGF intravesically (24), intrathecally (76), intramuscularly (77), or via adenovi- Fig.…”