Basic fibroblast growth factor causes urinary bladder overactivity through gap junction generation in the smooth muscle

Abstract

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 α-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.

Expression and functional activity of four myocardin isoforms

“…Rat aortic smooth muscle cells (RASMC) and rat bladder smooth muscle cells (RBSMC) were isolated using a procedure described previously (Chen et al, 2002;Kanematsu et al, 2005;Imamura et al, 2009). PAC1 cells (rat pulmonary artery SMC line) have been carefully characterized previously and shown to faithfully express a number of SMC-restricted genes (Firulli et al, 1998).…”

Altered Detrusor Gap Junction Communications Induce Storage Symptoms in Bladder Inflammation: A Mouse Cyclophosphamide-Induced Model of Cystitis

“…Previous studies demonstrated that gap junction proteins in the urothelium or detrusor smooth muscle of bladders function as key regulators for non-neurogenic mechanisms of various hyperactive bladder conditions [16], [17], [18], [19]. However, the role of gap junctions is still unclear in bladder inflammation.…”

“…Gap junction channels provide a cytoplasmic continuity between adjacent cells allowing the intercellular exchange of ions and metabolites [20]. Gap junctions consists of several connexins, and connexin 43 (GJA1) is one of the major components of gap junctions in bladders [16], [21]. Several studies indicating the relationship between inflammation and up-regulation of GJA1 in bladders strongly suggested that gap junction function was involved in pathological conditions underlying bladder inflammation [19], [22].…”

Myogenic bladder defects in mouse models of human oculodentodigital dysplasia

“…Previously, it has been clearly shown that Cx43 sensitizes the bladder for cyclic and circadium oscillations in bladder storage of urine and micturition [22,25,43,44]. Thus, on one hand, it is not surprising that rodent models of a hyperactive bladder suggest that this condition is correlated with increased levels of Cx43 and GJIC in the bladder [25,45].…”