Basic fibroblast growth factor causes urinary bladder overactivity through gap junction generation in the smooth muscle.
Overactive bladder is a highly prevalent clinical condition that is often caused by bladder outlet obstruction (BOO). Increased coupling of bladder smooth muscle cells (BSMC) via gap junctions has been hypothesized as a mechanism for myogenic bladder overactivity in BOO, although little is known about the regulatory system underlying such changes. Here, we report the involvement of basic fibroblast growth factor (bFGF) and connexin 43, a bladder gap junction protein, in bladder overactivity. BOO created by urethral constriction in rats resulted in elevated bFGF and connexin 43 levels in the bladder urothelium and muscle layer, respectively, and muscle strips from these bladders were more sensitive than those from sham-operated controls to a cholinergic agonist. In vitro bFGF treatment increased connexin 43 expression in cultured rat BSMC via the ERK 1/2 pathway. This finding was supported by another in vivo model, where bFGF released from gelatin hydrogels fixed on rat bladder walls caused connexin 43 upregulation and gap junction formation in the muscle layer. Bladder muscle strips in this model showed increased sensitivity to a cholinergic agonist that was blocked by inhibition of gap junction function with alpha-glycyrrhetinic acid. Cystometric analyses of this model showed typical features of detrusor overactivity such as significantly increased micturition frequency and decreased bladder capacity. These findings suggest that bFGF from the urothelium could induce bladder hypersensitivity to acetylcholine via gap junction generation in the smooth muscle, thereby contributing to the myogenic overactivity of obstructed bladders.
Imamura
Masaaki
M
Department of Urology, Graduate School of Medicine, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, 606-8507 Japan.
Negoro
Hiromitsu
H
Kanematsu
Akihiro
A
Yamamoto
Shingo
S
Kimura
Yu
Y
Nagane
Kentaro
K
Yamasaki
Toshinari
T
Kanatani
Isao
I
Ito
Noriyuki
N
Tabata
Yasuhiko
Y
Ogawa
Osamu
O
D000818:Animals; D002478:Cells, Cultured; D018031:Connexin 43 / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism* / Q000494:pharmacology; D017629:Gap Junctions / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D001743:Urinary Bladder / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D001748:Urinary Bladder Neck Obstruction / Q000150:complications; D053201:Urinary Bladder, Overactive / Q000209:etiology / Q000378:metabolism*
D018031:Connexin 43; D016222:Fibroblast Growth Factor 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3