Urogenital Alterations in Aged Male Caveolin-1 Knockout Mice

Woodman, Scott E.; Cheung, Michelle W.-C.; Tarr, Moses; North, Amanda; Schubert, William; Lagaud, Guy; Marks, Carolyn B.; Russell, Robert G.; Hassan, Ghada S.; Factor, Stephen M.; Christ, George J.; Lisanti, Michael P.

doi:10.1097/01.ju.0000105102.72295.b8

Cited by 74 publications

(101 citation statements)

References 22 publications

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“…Interestingly, alterations in bladder function in Cav-1 knockout mice have also been described. Signi¢cant bladder hypertrophy with increased voiding pressure, increased inter-micturition pressures and decreased carbachol and extracellular potassium induced contractions were demonstrated [Woodman et al, 2004]. A separate study described a similar decrease in bladder contractions elicited by electric stimulation or carbachol; in contrast however, bladders were markedly distended in these knockout animals, voiding contractions were signi¢cantly lower and the contractile response to extracellular potassium was unchanged [Lai et al, 2004].…”

Section: Discussionmentioning

confidence: 85%

“…For example, hypercalciuria and urolithiasis resulting from severely compromised renal calcium reabsorption have been described [Cao et al, 2003]. In the lower urinary tract, £uid accumulation in the prostate, seminal vesicles and kidneys associated with dilation and eventual necrosis was apparent and the prostates in these animals developed thickened ¢bromuscular stroma [Woodman et al, 2004]. Interestingly, alterations in bladder function in Cav-1 knockout mice have also been described.…”

Section: Discussionmentioning

confidence: 93%

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Smooth muscle caveolae differentially regulate specific agonist induced bladder contractions

Cristofaro

Peters

Yalla

et al. 2006

Neurourology and Urodynamics

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Aims: Caveolae are cholesterol-rich plasmalemmal microdomains that serve as sites for sequestration of signaling proteins and thus may facilitate, organize, and integrate responses to extracellular stimuli. While previous studies in the bladder have demonstrated alterations in caveolae with particular physiologic or pathologic conditions, little attention has been focused on the functional signi¢cance of these organelles. Therefore, the purpose of this study was to investigate the role of caveolae in the modulation of receptor-mediated signal transduction and determine the presence and localization of caveolin proteins in bladder tissue. Methods: Contractile responses to physiologic agonists were measured in rat bladder tissue before and after disruption of caveolae achieved by depleting membrane cholesterol with methyl-b-cyclodextrin. Stimulation with agonists was repeated after caveolae were restored as a result of cholesterol replenishment. RT-PCR, immmunohistochemistry, and Western blotting were used to determine the expression and localization of caveolin mRNA and proteins. Results: Following caveolae disruption, contractile responses to angiotensin II and serotonin were attenuated, whereas responses to bradykinin and phenylephrine were augmented. Cholesterol replenishment restored responses towards baseline. Carbachol and KCl induced contractions were not a¡ected by caveolae disruption. Ultrastructure analysis con¢rmed loss of caveolae following cholesterol depletion with cyclodextrin and caveolae restoration following cholesterol replacement. Gene and protein expression of caveolin-1, -2, and -3 was detected in bladder tissue. Immunoreactivity for all three caveolins was observed in smooth muscle cells throughout the bladder. Conclusions: The functional e¡ects of cholesterol depletion on speci¢c agonist-induced contractile events and the expression of all three caveolins in bladder smooth muscle support a central role for caveolae in regulation of selective G-protein-coupled receptor signaling pathways in bladder smooth muscle. Thus, caveolae serve to di¡erentially regulate bladder smooth muscle by a stimulus-dependent potentiation or inhibition of bladder contraction.

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Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 93%

Smooth muscle caveolae differentially regulate specific agonist induced bladder contractions

Cristofaro

Peters

Yalla

et al. 2006

Neurourology and Urodynamics

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“…63 Deletion of CAV1 leads to significant bladder dysfunction and urogenital organ changes in aged male mice. 30 In summary, the present study demonstrated that GATA-6 is a transcriptional repressor of both the human and murine CAV1 genes in BSM. In addition, a new mode of caveolin-1 gene regulation has been established in which the GATA motif on the CAV1 promoter mediates its cognate gene expression through GATA-6 recruitment to the promoter in these cells.…”

Section: Discussionmentioning

confidence: 91%

“…Mice with a disrupted CAV1 gene exhibit pronounced cardiovascular phenotypes including cardiomyopathy, severe pulmonary hypertension, and impaired BSM contraction. 60,30 Caveolae seem to constitute an important signaling domain that has a role not only in regulation of smooth muscle tone 64 but also in proliferation such as observed in neointima formation and atherosclerosis. 63 Deletion of CAV1 leads to significant bladder dysfunction and urogenital organ changes in aged male mice.…”

Section: Discussionmentioning

confidence: 99%

“…29 Consistent with these findings, caveolin-1 knockout mice fail to form caveolae, resulting in bladder hypertrophy and impaired bladder smooth muscle contraction. 30,31 Caveolin-1 protein expression is also reduced in hypertrophic smooth muscle in obstructed rabbit bladder. 6 Thus, it is possible that down-regulation of caveolin-1 expression in smooth muscle contributes to bladder dysfunction.…”

mentioning

confidence: 99%

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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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From embryonic development to human diseases: The functional role of caveolae/caveolin

Sohn

Brick

Tuan

2016

Birth Defects Research Pt C

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Caveolae, an almost ubiquitous, structural component of the plasma membrane, play a critical role in many functions essential for proper cell function, including membrane trafficking, signal transduction, extracellular matrix remodeling, and tissue regeneration. Three main types of caveolin proteins have been identified from caveolae since the discovery of caveolin-1 in the early 1990s. All three (Cav-1, Cav-2, and Cav-3) play crucial roles in mammalian physiology, and can effect pathogenesis in a wide range of human diseases. While many biological activities of caveolins have been uncovered since its discovery, their role and regulation in embryonic develop remain largely poorly understood, although there is increasing evidence that caveolins may be linked to lung and brain birth defects. Further investigations are clearly needed to decipher how caveolae/caveolins mediate cellular functions and activities of normal embryogenesis and how their perturbations contribute to developmental disorders.

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Urogenital Alterations in Aged Male Caveolin-1 Knockout Mice

Abstract: The loss of Cav-1 and, thus, of most smooth muscle cell caveolae results in significant bladder dysfunction and urogenital organ changes in aged male mice.

Cited by 74 publications

References 22 publications

Smooth muscle caveolae differentially regulate specific agonist induced bladder contractions

Smooth muscle caveolae differentially regulate specific agonist induced bladder contractions

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

From embryonic development to human diseases: The functional role of caveolae/caveolin

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