Strain history and TGF-β1 induce urinary bladder wall smooth muscle remodeling and elastogenesis

Abstract

Mechanical cues that trigger pathological remodeling in smooth muscle tissues remain largely unknown and are thought to be pivotal triggers for strain-induced remodeling. Thus, an understanding of the effects mechanical stimulation is important to elucidate underlying mechanisms of disease states and in the development of methods for smooth muscle tissue regeneration. For example, the urinary bladder wall (UBW) adaptation to spinal cord injury (SCI) includes extensive hypertrophy as well as increased collagen and elastin, all of which profoundly alter its mechanical response. In addition, the pro-fibrotic growth factor TGF-β1 is upregulated in pathologies of other smooth muscle tissues and may contribute to pathological remodeling outcomes. In the present study, we utilized an ex vivo organ culture system to investigate the response of UBW tissue under various strain-based mechanical stimuli and exogenous TGF-β1 to assess extracellular matrix (ECM) synthesis, mechanical responses, and bladder smooth muscle cell (BSMC) phenotype. Results indicated that a 0.5-Hz strain frequency triangular waveform stimulation at 15% strain resulted in fibrillar elastin production, collagen turnover, and a more compliant ECM. Further, this stretch regime induced changes in cell phenotype while the addition of TGF-β1 altered this phenotype. This phenotypic shift was further confirmed by passive strip biomechanical testing, whereby the bladder groups treated with TGF-β1 were more compliant than all other groups. TGF-β1 increased soluble collagen production in the cultured bladders. Overall, the 0.5-Hz strain-induced remodeling caused increased compliance due to elastogenesis, similar to that seen in early SCI bladders. Thus, organ culture of bladder strips can be used as an experimental model to examine ECM remodeling and cellular phenotypic shift and potentially elucidate BMSCs ability to produce fibrillar elastin using mechanical stretch either alone or in combination with growth factors.

S-Nitrosoglutathione protects the spinal bladder: Novel therapeutic approach to post-spinal cord injury bladder remodeling

“…In the present study, the cystometrogram obtained from rats on Day 2 and 14 post‐SCI did not show regular voiding contractions. Increased collagen deposition following SCI is known to induce bladder hypertrophy . We have also observed a significantly increased collagen content in the hypertrophying spinal bladder.…”

“…Increased collagen deposition following SCI is known to induce bladder hypertrophy. 30 We have also observed a significantly increased collagen content in the hypertrophying spinal bladder. On the other hand, GSNO treatment significantly decreased the bladder collagen level.…”

Modeling the influence of acute changes in bladder elasticity on pressure and wall tension during filling

“…The bladder strips were cut in the base-to-dome direction near the dome as previously described (Almasri, Ratz et al 2010); however bladders from a range of species include both longitudinal and circumferential layers of muscle bundles (Toosi, Nagatomi et al 2008, Heise, Parekh et al 2012). In most species, there are greater numbers of smooth muscle bundles running longitudinally, with two larger layers of longitudinal muscle bundles sandwiching a smaller layer of circumferential smooth muscle.…”

Combinational effects of muscarinic receptor inhibition and β3‐adrenoceptor stimulation on neurogenic bladder dysfunction in rats with spinal cord injury

“…It has been shown that both TGF‐β1 and bFGF are contributing factors to smooth muscle cell proliferation and differentiation and that activation of signaling pathways of these factors in the bladder leads to bladder wall fibrosis and stiffening following SCI . In vitro studies, bFGF also reportedly upregulates the expression of type 3 collagen .…”