Cyclic Pressure Stimulates DNA Synthesis through the PI3K/Akt Signaling Pathway in Rat Bladder Smooth Muscle Cells

Stover, Joshua D.; Nagatomi, Jiro

doi:10.1007/s10439-007-9331-9

Cited by 33 publications

(40 citation statements)

References 55 publications

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“…Postulated sensing mechanisms include cytoskeletal elements, extracellular matrix receptors, and/or membrane channels that trigger downstream signaling pathways. 25,32,39 Future research is needed to understand and elucidate cellular responses to elevated pressure and other mechanical forces.…”

Section: Future Workmentioning

confidence: 99%

Investigating the Role of Ischemia vs. Elevated Hydrostatic Pressure Associated with Acute Obstructive Uropathy

et al. 2009

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Obstructive uropathy can cause irreversible renal damage. It has been hypothesized that elevated hydrostatic pressure within renal tubules and/or renal ischemia contributes to cellular injury following obstruction. However, these assaults are essentially impossible to isolate in vivo. Therefore, we developed a novel pressure system to evaluate the isolated and coordinated effects of elevated hydrostatic pressure and ischemic insults on renal cells in vitro. Cells were subjected to: (1) elevated hydrostatic pressure (80 cm H(2)O); (2) ischemic insults (hypoxia (0% O(2)), hypercapnia (20% CO(2)), and 0 mM glucose media); and (3) elevated pressure + ischemic insults. Cellular responses including cell density, lactate dehydrogenase (LDH) release, and intracellular LDH (LDH(i)), were recorded after 24 h of insult and following recovery. Data were analyzed to assess the primary effects of ischemic insults and elevated pressure. Unlike pressure, ischemic insults exerted a primary effect on nearly all response measurements. We also evaluated the data for insult interactions and identified significant interactions between ischemic insults and pressure. Altogether, findings indicate that pressure may sub-lethally effect cells and alter cellular metabolism (LDH(i)) and membrane properties. Results suggest that renal ischemia may be the primary, but not the sole, cause of cellular injury induced by obstructive uropathy.

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Section: Future Workmentioning

confidence: 99%

Investigating the Role of Ischemia vs. Elevated Hydrostatic Pressure Associated with Acute Obstructive Uropathy

et al. 2009

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“…AoSMCs were treated with vehicle control (dimethyl sulfoxide), 100 nmol/L rapamycin, 26 10 mol/L UO126, 27 or 20 mol/L LY-294002. 28 Rapamycin, U0126, and LY294002 were purchased from LC Laboratories (Woburn, Mass). The cell proliferation rate was determined with use of the WST-1 cleavage-based cell proliferation (Chemicon International, Temecula, Calif) as described.…”

Section: Cell Proliferation Assaymentioning

confidence: 99%

NF1 Regulates a Ras-Dependent Vascular Smooth Muscle Proliferative Injury Response

Ismat

Wang

et al. 2007

Circulation

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Background-Neurofibromatosis type I (NF1) is a common autosomal dominant disorder with a broad array of clinical manifestations, including benign and malignant tumors, osseous dysplasias, and characteristic cutaneous findings. In addition, NF1 patients have an increased incidence of cardiovascular diseases, including obstructive vascular disorders. In animal models, endothelial expression of the disease gene, NF1, is critical for normal heart development. However, the pathogeneses of the more common vascular disorders are not well characterized. Methods and Results-To examine the role of NF1 in vascular smooth muscle, we generated mice with homozygous loss of the murine homolog Nf1 in smooth muscle (Nf1smKO). These mice develop and breed normally. However, in response to vascular injury, they display a marked intimal hyperproliferation and abnormal activation of mitogenactivated protein kinase, a downstream effector of Ras. Vascular smooth muscle cells cultured from these mice also display enhanced proliferation and mitogen-activated protein kinase activity. Smooth muscle expression of the NF1 Ras-regulatory domain (GTPase activating protein-related domain) rescues intimal hyperplasia in Nf1smKO mice and normalizes vascular smooth muscle cell Ras effector activity and proliferation in vitro, similar to blockade of downstream effectors of Ras. Conclusions-In this in vivo model of NF1 obstructive vascular disease, we have shown that Nf1 regulation of Ras plays a critical role in vascular smooth muscle proliferation after injury. These results suggest opportunities for targeted therapeutics in the prevention and treatment of NF1-related vascular disease and in the treatment of neointimal proliferation in other settings.

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“…The surmounting evidence of bladder SMC mechanotransduction includes, but is not limited to, increased expressions of heparin-binding epidermal growth factor (HB-EGF) and cyclooxygenase-2 (COX-2) 15,17-19 and activation of p38 SAPK2 and PI3K/Akt intracellular signaling pathways. 2,15,23 These results suggest that multiple signaling pathways may be concomitantly at work in response to the applied mechanical stimuli. Thus, the conventional reductionist approach that examines only one or two molecules at a time may not fully uncover the complexity of the cellular mechanotransduction events.…”

Section: Introductionmentioning

confidence: 81%

“…1). 23 SMC maintained under static (atmospheric pressure) conditions for the duration of the experiment were used as the control. This set of parameters was chosen because in our previous study the earliest molecular response by SMC to the cyclic pressure was detected at the 1 h time point.…”

Section: Exposure Of Rat Smc To Cyclic Pressurementioning

confidence: 99%

“…4 Using an in vitro model, our laboratory recently demonstrated that when bladder smooth muscle cells (SMC) were exposed to a pathological level of cyclic pressure (0.1 Hz, 40 cmH 2 O) for up to 24 consecutive hours, the cells exhibited increased cell proliferation that was mediated, at least in part, by activation of the PI3K/Akt pathway. 23 In addition to cyclic pressure, other forms of mechanical stimuli, cyclic stretch (max 20% at 0.1 Hz) 2,8,16 and sustained hydrostatic pressure (up to 40 cmH 2 O), 3,9,10 have also been shown to trigger cellular responses pertinent to mechanically triggered bladder remodeling. The surmounting evidence of bladder SMC mechanotransduction includes, but is not limited to, increased expressions of heparin-binding epidermal growth factor (HB-EGF) and cyclooxygenase-2 (COX-2) 15,17-19 and activation of p38 SAPK2 and PI3K/Akt intracellular signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

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Proteomic Analysis of Bladder Smooth Muscle Cell Response to Cyclic Hydrostatic Pressure

Nagatomi

Gray

2009

Cel. Mol. Bioeng.

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We and other laboratories previously demonstrated that multiple signaling pathways are at work in SMC responses to applied mechanical stimuli, indicating the need for a high-throughput approach to study the complex mechanotransduction mechanism. In the present study, the feasibility of proteomic techniques to examine the mechanotransduction of bladder smooth muscle cells (SMC) was tested for the first time. Specifically, two-dimensional (2D) gel electrophoresis and image analyses were employed to separate and identify protein profiles in control and in cells exposed to cyclic pressure (0.1 Hz, 40 cmH 2 O) for 1 h. The results provide evidence that 20 (out of 155) spots exhibited changes (up-or down-regulation) in intensity between control and cyclic pressure groups. The mass spectrometry analysis provided sequences for 118 tryptic peptides from these 20 spots, and peptide mapping provided a positive match of peptide sequences to 24 distinct proteins. Moreover, the results of Western analysis independently confirmed up-regulation of nuclear matrix protein, lamin A/C in SMC exposed to cyclic pressure. Since the protein samples were predominantly of the cytosolic fraction, we concluded that the observed up-regulation was due to the translocation of either membrane-bound or nuclear localized proteins into the cytosol. Based on these observations, the present study demonstrated that the proteomic approach can be a powerful analytical tool for mechanobiology research that allows analysis of a large number of variables, thereby supporting development of new hypotheses to guide future investigation.

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Cyclic Pressure Stimulates DNA Synthesis through the PI3K/Akt Signaling Pathway in Rat Bladder Smooth Muscle Cells

Cited by 33 publications

References 55 publications

Investigating the Role of Ischemia vs. Elevated Hydrostatic Pressure Associated with Acute Obstructive Uropathy

Investigating the Role of Ischemia vs. Elevated Hydrostatic Pressure Associated with Acute Obstructive Uropathy

NF1 Regulates a Ras-Dependent Vascular Smooth Muscle Proliferative Injury Response

Proteomic Analysis of Bladder Smooth Muscle Cell Response to Cyclic Hydrostatic Pressure

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