Overexpression of NGF in mouse urothelium leads to neuronal hyperinnervation, pelvic sensitivity, and changes in urinary bladder function.
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.
Schnegelsberg
Birthe
B
Department of Neuroscience, Roche Palo Alto, Palo Alto, California, USA.
Sun
Tung-Tien
TT
Cain
Gary
G
Bhattacharya
Anindya
A
Nunn
Philip A
PA
Ford
Anthony P D W
AP
Vizzard
Margaret A
MA
Cockayne
Debra A
DA
D000818:Animals; D001835:Body Weight; D003556:Cystitis / Q000473:pathology / Q000503:physiopathology; D015870:Gene Expression / Q000502:physiology; D008407:Mast Cells / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009130:Muscle, Smooth / Q000294:innervation / Q000473:pathology / Q000502:physiology; D020932:Nerve Growth Factor / Q000235:genetics* / Q000378:metabolism; D009929:Organ Size; D012333:RNA, Messenger / Q000378:metabolism; D012020:Reflex, Abdominal / Q000502:physiology; D011984:Sensory Receptor Cells / Q000473:pathology / Q000502:physiology; D013564:Sympathetic Nervous System / Q000473:pathology / Q000503:physiopathology; D001743:Urinary Bladder / Q000294:innervation / Q000473:pathology / Q000502:physiology*; D053201:Urinary Bladder, Overactive / Q000473:pathology / Q000503:physiopathology*; D014554:Urination / Q000502:physiology; D060170:Uroplakin II; D019459:Urothelium / Q000294:innervation / Q000473:pathology / Q000502:physiology*
D008565:Membrane Proteins; D012333:RNA, Messenger; C554659:Upk2 protein, mouse; D060170:Uroplakin II; D020932:Nerve Growth Factor