Department of Neuroscience, Roche Palo Alto, Palo Alto, California, USA.
Am J Physiol Regul Integr Comp Physiol. 2010 Mar;298(3):R534-47. doi: 10.1152/ajpregu.00367.2009. Epub 2009 Dec 23.
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.
NGF 被认为通过介导炎症，以及感觉和交感神经元在支配膀胱的形态和功能变化，在膀胱功能障碍中发挥作用。为了进一步探讨 NGF 在膀胱感觉功能中的作用，我们使用尿路上皮特异性尿路上皮蛋白 II (UPII) 启动子在膀胱中生成了一种慢性 NGF 过表达的转基因小鼠模型。与野生型同窝对照相比，NGF 过表达（NGF-OE）转基因小鼠从出生后第 7 天到 12-16 周龄时，膀胱中 NGF mRNA 和蛋白表达水平更高。NGF 的过表达导致膀胱增大，其特征是黏膜下和逼尿肌平滑肌中的神经纤维增生明显，组织肥大细胞数量增加。CGRP 和 P 物质阳性 C 纤维感觉传入、神经丝 200 阳性有髓感觉传入和位于 suburothelial 神经丛中的酪氨酸羟化酶阳性交感神经纤维的密度显著增加。CGRP 阳性神经节也存在于转基因小鼠的膀胱中。在清醒的开式排尿测压法中，转基因小鼠的膀胱容量减小，非排尿性膀胱收缩的数量和幅度增加。这些膀胱功能的变化与躯体骨盆过敏的增加有关。因此，转基因小鼠中慢性尿路上皮 NGF 过表达导致神经元增殖、膀胱肥大细胞局部增加、膀胱反射活动增加和骨盆过敏。因此，NGF 过表达小鼠可能为探索 NGF 在膀胱功能障碍中的作用提供了一个有用的转基因模型。
