A Male Murine Model of Partial Bladder Outlet Obstruction Reveals Changes in Detrusor Morphology, Contractility and Myosin Isoform Expression

Austin, J. Christopher; Chacko, Samuel; DiSanto, Michael E.; Canning, Douglas A.; Zderic, Stephen A.

doi:10.1097/01.ju.0000138045.61378.96

Cited by 49 publications

(58 citation statements)

References 15 publications

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“…Thus, the further decrease of SM2 and altered SM2:SM1 ratio was not the reason, but rather the result of obstruction in lower urinary tract. Indeed, a decreased ratio of SM2 : SM1 has been previously found in bladders with partial obstruction of bladder outlet, and this has been considered as a phenotypic marker of smooth muscle hypertrophy (Cher et al, 1996;Gomes et al, 2000;Burkhard et al, 2001;Hypolite et al, 2001;Austin et al, 2004). Thus, a further decrease of SM2 or reduced ratio of SM2:SM1 in SM2…”

Section: Discussionmentioning

confidence: 92%

“…However, the expression level of SM2 alters in a variety of pathological conditions. For example, decreased expression of SM2 has been reported in obstructed urinary bladder of rabbit and rat (Chacko and Longhurst, 1994;Wang et al, 1995;Cher et al, 1996;Gomes et al, 2000;Lin et al, 2000;DiSanto et al, 2003;Austin et al, 2004), in pulmonary arteries of primary pulmonary hypertension (Packer et al, 1998;Itoh et al, 2002), and in neointimal smooth muscle cells of injured or atherosclerotic vessels (Aikawa et al, 1993). On the other hand, in myometrium of ovariectomized rabbits SM2 has been found to increase, yet such an alteration can be normalized by estrogen treatment (Capriani et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

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SM2+/- male mice are predisposed to develop urinary tract obstruction and hyper contractility of the bladder smooth muscle upon ageing

Chi

Zhou

Sopariwala

et al. 2011

J. Smooth Muscle Res.

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We previously showed that complete loss of smooth muscle myosin heavy chain isoform 2 (SM2) resulted in postnatal lethality, but in het mice a partial loss of SM2 (SM2 +/-) was accompanied by down-regulation of SM1 with unaltered SM2:SM1 ratio. To determine whether a normal bladder function would be maintained throughout its lifespan, we aged WT and SM2 +/-mice up to 18 months and analyzed a) SM2:SM1 ratio b) bladder smooth muscle structure and c) function in SM2 +/-het mice. A notable finding was that ~50% of 15-18 months old male SM2 +/-mice exhibited urinary retention in bladder with the distention of upper urethra. In SM2 +/-mouse bladder with urinary retention, the SM2:SM1 ratio was decreased but not in SM2 +/-mouse bladder that did not develop urinary retention. Interestingly in the distended bladder the expression levels of -actin and tropomyosin remained unaltered despite a reduction in the number of myosin thick filaments. These distended bladders showed hypersensitivity to submaximal K + depolarization and M3-receptor stimulation, without a significant increase in myosin light chain phosphorylation. We therefore suggest that a partial loss of SM2 may predispose male mice to develop lower urinary tract obstruction during ageing. In addition our data suggest that bladder obstruction can cause a further reduction in SM2 expression and SM2:SM1 ratio, and a hyper-contractility of the bladder smooth muscle.

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Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

SM2+/- male mice are predisposed to develop urinary tract obstruction and hyper contractility of the bladder smooth muscle upon ageing

Chi

Zhou

Sopariwala

et al. 2011

J. Smooth Muscle Res.

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“…Hence primary defect may lie in myosin filament. In laboratory animals, 21,22 SMMHC expression has been one of the most sensitive and specific moleuclar markers for phenotypic alteration in smooth muscle cells and associated with dysfunction in a variety of pathological conditions. [23][24][25][26] Likewise, in the human, SMMHC may also be a sensitive and reliable marker for smooth muscle cell alteration.…”

Section: Involvementmentioning

confidence: 99%

Molecular and Cellular Characteristics of the Colonic Pseudo-obstruction in Patients With Intractable Constipation

Suh

Myung

Kwak

et al. 2015

J Neurogastroenterol Motil

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Background/AimsChronic intestinal pseudo-obstruction (CIPO) is a disorder characterized by recurrent symptoms suggestive of obstruction such as abdominal pain, proximal distension with extremely suppressed motility in the absence of lumen-occluding lesion, whose etiology/pathophysiology is poorly understood. In this study we investigated a functionally obstructive lesion that could underlie symptoms of CIPO. MethodsWe studied colons surgically removed from 13 patients exhibiting clinical/pathological features of pseudo-obstruction but were unresponsive to standard medical treatments. The colons were characterized morphologically, functionally and molecularly, which were compared between regions and to 28 region-matched controls obtained from colon cancer patients. ResultsThe colons with pseudo-obstruction exhibited persistent luminal distension proximally, where the smooth muscle was hypertrophied with changes in the cell phenotypes. Distinct luminal narrowing was observed near the distal end of the dilated region, close to the splenic flexure, previously referred to as the "transition zone (TZ)" between the dilated and non-dilated loops. Circular muscles from the TZ responded less to depolarization and cholinergic stimulation, which was associated with downregulation of L-type calcium channel expression. Smooth muscle contractile protein was also downregulated. Myenteric ganglia and neuronal nitric oxide synthase (nNOS) positive cells were deficient, more severely in the TZ region. Interstitial cells of Cajal was relatively less affected. 561 ConclusionsThe TZ may be the principal site of functional obstruction, leading to proximal distension and smooth muscle hypertrophy, in which partial nNOS depletion could play a key role. The neuromuscular abnormalities probably synergistically contributed to the extremely suppressed motility observed in the colonic pseudo-obstruction.(J Neurogastroenterol Motil 2015;21:560-570)

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“…Adult male mice were subjected to partial surgical ligation of the urethra, as previously described. 35 Sham-operated animals underwent an identical procedure until the suture was tied down, at which point the suture was removed and the abdomen closed. After the desired times, the mice were anesthetized as before, the bladder was harvested, and the BSM layer was separated from the mucosa and serosa.…”

Section: Surgical Induction Of Pboo In a Mouse Modelmentioning

confidence: 99%

Transcriptional Repression of Caveolin-1 (CAV1) Gene Expression by GATA-6 in Bladder Smooth Muscle Hypertrophy in Mice and Human Beings

Boopathi

Gomes

Goldfarb

et al. 2011

The American Journal of Pathology

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Hypertrophy occurs in urinary bladder wall smooth muscle (BSM) in men with partial bladder outlet obstruction (PBOO) caused by benign prostatic hyperplasia (BPH) and in animal models of PBOO. Hypertrophied BSM from the rabbit model exhibits downregulation of caveolin-1, a structural and functional protein of caveolae that function as signaling platforms to mediate interaction between receptor proteins and adaptor and effector molecules to regulate signal generation, amplification, and diversification. Caveolin-1 expression is diminished in PBOO-induced BSM hypertrophy in mice and in men with BPH. The proximal promoter of the human and mouse caveolin-1 (CAV1) gene was characterized, and it was observed that the transcription factor GATA-6 binds this promoter, causing reduced expression of caveolin-1. Furthermore, caveolin-1 expression levels inversely correlate with the abundance of GATA-6 in BSM hypertrophy in mice and human beings. Benign prostatic hyperplasia (BPH) is common in aging men and is often associated with lower urinary tract symptoms. Partial bladder outlet obstruction (PBOO) has long been considered a key factor in the mechanism through which BPH causes lower urinary tract symptoms. PBOO-induced lower urinary tract symptoms are associated with bladder wall smooth muscle (BSM) remodeling including hypertrophy, thereby altering bladder contractility.

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A Male Murine Model of Partial Bladder Outlet Obstruction Reveals Changes in Detrusor Morphology, Contractility and Myosin Isoform Expression

Abstract: Our male mouse model of PBOO demonstrates an increase in bladder mass, larger capacity and significantly decreased pressure generation in the in vitro whole bladder model. Obstruction induced increases in the expression of C-terminal (SM1) and N-terminal (SM-A) myosin heavy chain isoforms.

Cited by 49 publications

References 15 publications

SM2+/- male mice are predisposed to develop urinary tract obstruction and hyper contractility of the bladder smooth muscle upon ageing

SM2+/- male mice are predisposed to develop urinary tract obstruction and hyper contractility of the bladder smooth muscle upon ageing

Molecular and Cellular Characteristics of the Colonic Pseudo-obstruction in Patients With Intractable Constipation

Transcriptional Repression of Caveolin-1 (CAV1) Gene Expression by GATA-6 in Bladder Smooth Muscle Hypertrophy in Mice and Human Beings

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