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Michael R. King - One of the best experts on this subject based on the ideXlab platform.
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lamin a c deficiency reduces circulating tumor cell resistance to Fluid Shear Stress
American Journal of Physiology-cell Physiology, 2015Co-Authors: Michael J. Mitchell, Celine Denais, Maxine F Chan, Zhexiao Wang, Jan Lammerding, Michael R. KingAbstract:Metastasis contributes to over 90% of cancer-related deaths and is initiated when cancer cells detach from the primary tumor, invade the basement membrane, and enter the circulation as circulating tumor cells (CTCs). While metastasis is viewed as an inefficient process with most CTCs dying within the bloodstream, it is evident that some CTCs are capable of resisting hemodynamic Shear forces to form secondary tumors in distant tissues. We hypothesized that nuclear lamins A and C (A/C) act as key structural components within CTCs necessary to resist destruction from elevated Shear forces of the bloodstream. Herein, we show that, compared with nonmalignant epithelial cells, tumor cells are resistant to elevated Fluid Shear forces in vitro that mimic those within the bloodstream, as evidenced by significant decreases in cellular apoptosis and necrosis. Knockdown of lamin A/C significantly reduced tumor cell resistance to Fluid Shear Stress, with significantly increased cell death compared with parental tumor cell and nontargeting controls. Interestingly, lamin A/C knockdown increased Shear Stress-induced tumor cell apoptosis, but did not significantly affect cellular necrosis. These data demonstrate that lamin A/C is an important structural component that enables tumor cell resistance to Fluid Shear Stress-mediated death in the bloodstream, and may thus facilitate survival and hematogenous metastasis of CTCs.
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cooperative effects of matrix stiffness and Fluid Shear Stress on endothelial cell behavior
Biophysical Journal, 2015Co-Authors: Julie C Kohn, Michael J. Mitchell, Michael R. King, Dennis W Zhou, Francois Bordeleau, Allen L Zhou, Brooke N Mason, Cynthia A ReinhartkingAbstract:Arterial hemodynamic Shear Stress and blood vessel stiffening both significantly influence the arterial endothelial cell (EC) phenotype and atherosclerosis progression, and both have been shown to signal through cell-matrix adhesions. However, the cooperative effects of Fluid Shear Stress and matrix stiffness on ECs remain unknown. To investigate these cooperative effects, we cultured bovine aortic ECs on hydrogels matching the elasticity of the intima of compliant, young, or stiff, aging arteries. The cells were then exposed to laminar Fluid Shear Stress of 12 dyn/cm2. Cells grown on more compliant matrices displayed increased elongation and tighter EC-cell junctions. Notably, cells cultured on more compliant substrates also showed decreased RhoA activation under laminar Shear Stress. Additionally, endothelial nitric oxide synthase and extracellular signal-regulated kinase phosphorylation in response to Fluid Shear Stress occurred more rapidly in ECs cultured on more compliant substrates, and nitric oxide production was enhanced. Together, our results demonstrate that a signaling cross talk between stiffness and Fluid Shear Stress exists within the vascular microenvironment, and, importantly, matrices mimicking young and healthy blood vessels can promote and augment the atheroprotective signals induced by Fluid Shear Stress. These data suggest that targeting intimal stiffening and/or the EC response to intima stiffening clinically may improve vascular health.
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Fluid Shear Stress Increases Neutrophil Activation via Platelet-Activating Factor
Biophysical Journal, 2014Co-Authors: Michael J. Mitchell, Michael R. KingAbstract:Leukocyte exposure to hemodynamic Shear forces is critical for physiological functions including initial adhesion to the endothelium, the formation of pseudopods, and migration into tissues. G-protein coupled receptors on neutrophils, which bind to chemoattractants and play a role in neutrophil chemotaxis, have been implicated as Fluid Shear Stress sensors that control neutrophil activation. Recently, exposure to physiological Fluid Shear Stresses observed in the microvasculature was shown to reduce neutrophil activation in the presence of the chemoattractant formyl-methionyl-leucyl-phenylalanine. Here, however, human neutrophil preexposure to uniform Shear Stress (0.1–2.75 dyn/cm2) in a cone-and-plate viscometer for 1–120 min was shown to increase, rather than decrease, neutrophil activation in the presence of platelet activating factor (PAF). Fluid Shear Stress exposure increased PAF-induced neutrophil activation in terms of L-selectin shedding, αMβ2 integrin activation, and morphological changes. Neutrophil activation via PAF was found to correlate with Fluid Shear Stress exposure, as neutrophil activation increased in a Shear Stress magnitude- and time-dependent manner. These results indicate that Fluid Shear Stress exposure increases neutrophil activation by PAF, and, taken together with previous observations, differentially controls how neutrophils respond to chemoattractants.
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computational and experimental models of cancer cell response to Fluid Shear Stress
Frontiers in Oncology, 2013Co-Authors: Michael J. Mitchell, Michael R. KingAbstract:It has become evident that mechanical forces play a key role in cancer metastasis, a complex series of steps that is responsible for the majority of cancer-related deaths. One such force is Fluid Shear Stress, exerted on circulating tumor cells (CTCs) by blood flow in the vascular microenvironment, and also on tumor cells exposed to slow interstitial flows in the tumor microenvironment. Computational and experimental models have the potential to elucidate metastatic cell behavior exposed to such forces. Here, we review the Fluid-generated forces that tumor cells are exposed to in the vascular and tumor microenvironments, and discuss recent computational and experimental models that have revealed mechanotransduction phenomena that may play a role in the metastatic process.
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Fluid Shear Stress sensitizes cancer cells to receptor mediated apoptosis via trimeric death receptors
New Journal of Physics, 2013Co-Authors: Michael J. Mitchell, Michael R. KingAbstract:Cancer metastasis, the process of cancer cell migration from a primary to distal location, typically leads to a poor patient prognosis. Hematogenous metastasis is initiated by intravasation of circulating tumor cells (CTCs) into the bloodstream, which are then believed to adhere to the luminal surface of the endothelium and extravasate into distal locations. Apoptotic agents such as tumor necrosis factor (TNF) apoptosis-inducing ligand (TRAIL), whether in soluble ligand form or expressed on the surface of natural killer (NK) cells, have shown promise in treating CTCs to reduce the probability of metastasis. The role of hemodynamic Shear forces in altering the cancer cell response to receptor-mediated apoptosis has not been previously investigated. Here, we report that human colon cancer COLO 205 and prostate cancer PC-3 cells exposed to a uniform Fluid Shear Stress in a cone-and-plate viscometer become sensitized to TRAIL-induced apoptosis. Shear-induced sensitization directly correlated with the application of Fluid Shear Stress, and TRAIL-induced apoptosis increased in a Fluid Shear Stress force- and time-dependent manner. In contrast, TRAIL-induced necrosis was not affected by the application Fluid Shear Stress. Interestingly, Fluid Shear Stress did not sensitize cancer cells to apoptosis when treated with doxorubicin, which also induces apoptosis in cancer cells. Caspase inhibition experiments revealed that Shear Stress-induced sensitization to TRAIL occurs via caspase-dependent apoptosis. These results suggest that physiological Fluid Shear force can modulate receptor-mediated apoptosis of cancer cells in the presence of apoptotic agents.
Rudi Busse - One of the best experts on this subject based on the ideXlab platform.
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phosphorylation and activation of the endothelial nitric oxide synthase by Fluid Shear Stress
Acta Physiologica Scandinavica, 2000Co-Authors: Beate Fisslthaler, Stefanie Dimmeler, Corinna Hermann, Rudi Busse, Ingrid FlemingAbstract:Fluid Shear Stress activates the endothelial nitric oxide (NO) synthase (eNOS) by a mechanism which does not require an increase in the intracellular concentration of free Ca2+ ([Ca2+]i), and is sensitive to several kinase inhibitors. Although phosphorylation of eNOS has been suggested to regulate enzyme activity, the mechanism of eNOS activation is still unclear. Here we demonstrate that Fluid Shear Stress elicits the phosphorylation of eNOS on tyrosine and serine residues. Inhibition of phosphatidylinositol 3-kinase (PI3K), using wortmannin or a dominant negative mutant of its downstream target, Akt (protein kinase B), prevented the maintained serine phosphorylation and activation of eNOS. Enhancing eNOS phosphorylation by inhibiting serine/threonine phosphatases, increased eNOS activity by approximately twofold, as assessed by the accumulation of intracellular cyclic GMP, without increasing the intracellular concentration of free Ca2+. These data suggest that Shear Stress activates a pathway involving PI3K and the serine/threonine kinase Akt, which phosphorylates eNOS. This phosphorylation directly increases eNOS activity at resting [Ca2+]i, thus rendering the Shear Stress-induced activation of eNOS apparently Ca2+-independent.
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ca2 independent activation of the endothelial nitric oxide synthase in response to tyrosine phosphatase inhibitors and Fluid Shear Stress
Circulation Research, 1998Co-Authors: Ingrid Fleming, Beate Fisslthaler, Johann Bauersachs, Rudi BusseAbstract:Abstract—Fluid Shear Stress enhances NO formation via a Ca2+-independent tyrosine kinase inhibitor–sensitive pathway. In the present study, we investigated the effects of the protein tyrosine phosphatase inhibitor phenylarsine oxide and of Fluid Shear Stress on endothelial NO production as well as on the membrane association and phosphorylation of the NO synthase (NOS) III. Phenylarsine oxide (10 μmol/L) induced an immediate and maintained NO-mediated relaxation of isolated rabbit carotid arteries, which was insensitive to the removal of extracellular Ca2+ and the calmodulin antagonist calmidazolium. This phenylarsine oxide–induced vasodilatation was unaffected by genistein but abrogated by the tyrosine kinase inhibitor erbstatin A. Incubation of native or cultured endothelial cells with phenylarsine oxide resulted in a time-dependent tyrosine phosphorylation of mainly Triton X-100–insoluble (cytoskeletal) proteins, along with a parallel change in the detergent solubility of NOS III, such that the enzyme ...
John A. Frangos - One of the best experts on this subject based on the ideXlab platform.
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g protein coupled receptors sense Fluid Shear Stress in endothelial cells
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Mirianas Chachisvilis, Yanliang Zhang, John A. FrangosAbstract:Hemodynamic Shear Stress stimulates a number of intracellular events that both regulate vessel structure and influence development of vascular pathologies. The precise molecular mechanisms by which endothelial cells transduce this mechanical stimulus into intracellular biochemical response have not been established. Here, we show that mechanical perturbation of the plasma membrane leads to ligand-independent conformational transitions in a G protein-coupled receptor (GPCR). By using time-resolved fluorescence microscopy and GPCR conformation-sensitive FRET we found that stimulation of endothelial cells with Fluid Shear Stress, hypotonic Stress, or membrane Fluidizing agent leads to a significant increase in activity of bradykinin B2 GPCR in endothelial cells. The GPCR conformational dynamics was detected by monitoring redistribution of GPCRs between inactive and active conformations in a single endothelial cell under Fluid Shear Stress in real time. We show that this response can be blocked by a B2-selective antagonist. Our data demonstrate that changes in cell membrane tension and membrane Fluidity affect conformational dynamics of GPCRs. Therefore, we suggest that GPCRs are involved in mediating primary mechanochemical signal transduction in endothelial cells. We anticipate our experiments to be a starting point for more sophisticated studies of the effects of changes in lipid bilayer environment on GPCR conformational dynamics. Furthermore, because GPCRs are a major target of drug development, a detailed characterization of mechanochemical signaling via the GPCR pathway will be relevant for the development of new antiatherosclerosis drugs.
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Fluorescent molecular rotor for the study of membrane Fluidity in endothelial cells under Fluid Shear Stress
Optical Diagnostics of Living Cells III, 2000Co-Authors: Mark A. Haidekker, John A. FrangosAbstract:Molecular rotors are fluorescent probes that change quantum yield with the viscosity of their environment. When integrated into the cell membrane, they can be used to probe viscosity changes of the membrane. Fluid Shear Stress is hypothesized to increase membrane Fluidity in the membrane of endothelial cells, a change that leads to the activation of heterotrimetric G proteins, thus activating a signal transduction cascade. This hypothesis was examined using a molecular rotor, 9-dicyanovinyl-julolidine (DCVJ) as membrane probe. The principal response, a decease of fluorescence intensity caused by increased membrane Fluidity, was obtained by adding a Fluidity-increasing agent to the cells. In a parallel-plate flow chamber, a confluent layer of DCVJ-labeled human umbilical cord venous endothelial cells were exposed to different levels of Fluid Shear Stress. With increased Shear, a reduced fluorescence intensity was observed, indicating an increase of membrane Fluidity. Step changes of Fluid Shear Stress caused an approximately linear drop of fluorescence within 5 seconds, showing fast and almost full recovery after Shear stopped. A linear relationship between Shear Stress and membrane Fluidity changes was also observed. This study not only shows the suitability of the molecular rotor DCVJ as a membrane Fluidity probe, but also provides evidence for the direct link between Fluid Shear Stress and membrane Fluidity, and suggests that the membrane is the primary flow mechanosensor of the cell.
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modulation of gtpase activity of g proteins by Fluid Shear Stress and phospholipid composition
Proceedings of the National Academy of Sciences of the United States of America, 1998Co-Authors: Sivaramaprasad Gudi, John P Nolan, John A. FrangosAbstract:Mechanical forces arising from strain, pressure, and Fluid Shear Stress are sensed by cells through an unidentified mechanoreceptor(s) coupled to intracellular signaling pathways. In vascular endothelial cells, Fluid Shear Stress is transduced via pathway(s) involving heterotrimeric guanine nucleotide-binding proteins (G proteins) by molecular mechanisms that are unknown. In the present study, we investigated the activation of purified G proteins reconstituted into phospholipid vesicles. Vesicles containing G proteins were loaded with [γ-32P]GTP and subjected to physiological levels of Fluid Shear Stress in a cone-and-plate viscometer. Steady-state GTP hydrolysis was measured as an index of G protein function. Shear Stress (0–30 dynes/cm2) activated G proteins in dose-dependent manner (0.48–4.6 pmol/min per μg of protein). Liposomes containing lysophosphatidylcholine (30 mol %) or treated with benzyl alcohol (40 mM), conditions that increase bilayer Fluidity, exhibited 3- to 5-fold enhancement of basal GTPase activity. Conversely, incorporation of cholesterol (24 mol %) into liposomes reduced the activation of G proteins by Shear. These results demonstrate the ability of the phospholipid bilayer to mediate the Shear Stress-induced activation of membrane-bound G proteins in the absence of protein receptors and that bilayer physical properties modulate this response.
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Fluid Shear Stress Stimulates Membrane Phospholipid Metabolism in Cultured Human Endothelial Cells
Journal of Vascular Research, 1992Co-Authors: Avilala Bhagyalakshmi, Francois Berthiaume, Kathleen M. Reich, John A. FrangosAbstract:There is evidence suggesting that Fluid Shear Stress activates phospholipid turnover in endothelial cells, but it is not clear which phospholipids are involved in the transduction of the flow signal.
Ingrid Fleming - One of the best experts on this subject based on the ideXlab platform.
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phosphorylation and activation of the endothelial nitric oxide synthase by Fluid Shear Stress
Acta Physiologica Scandinavica, 2000Co-Authors: Beate Fisslthaler, Stefanie Dimmeler, Corinna Hermann, Rudi Busse, Ingrid FlemingAbstract:Fluid Shear Stress activates the endothelial nitric oxide (NO) synthase (eNOS) by a mechanism which does not require an increase in the intracellular concentration of free Ca2+ ([Ca2+]i), and is sensitive to several kinase inhibitors. Although phosphorylation of eNOS has been suggested to regulate enzyme activity, the mechanism of eNOS activation is still unclear. Here we demonstrate that Fluid Shear Stress elicits the phosphorylation of eNOS on tyrosine and serine residues. Inhibition of phosphatidylinositol 3-kinase (PI3K), using wortmannin or a dominant negative mutant of its downstream target, Akt (protein kinase B), prevented the maintained serine phosphorylation and activation of eNOS. Enhancing eNOS phosphorylation by inhibiting serine/threonine phosphatases, increased eNOS activity by approximately twofold, as assessed by the accumulation of intracellular cyclic GMP, without increasing the intracellular concentration of free Ca2+. These data suggest that Shear Stress activates a pathway involving PI3K and the serine/threonine kinase Akt, which phosphorylates eNOS. This phosphorylation directly increases eNOS activity at resting [Ca2+]i, thus rendering the Shear Stress-induced activation of eNOS apparently Ca2+-independent.
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ca2 independent activation of the endothelial nitric oxide synthase in response to tyrosine phosphatase inhibitors and Fluid Shear Stress
Circulation Research, 1998Co-Authors: Ingrid Fleming, Beate Fisslthaler, Johann Bauersachs, Rudi BusseAbstract:Abstract—Fluid Shear Stress enhances NO formation via a Ca2+-independent tyrosine kinase inhibitor–sensitive pathway. In the present study, we investigated the effects of the protein tyrosine phosphatase inhibitor phenylarsine oxide and of Fluid Shear Stress on endothelial NO production as well as on the membrane association and phosphorylation of the NO synthase (NOS) III. Phenylarsine oxide (10 μmol/L) induced an immediate and maintained NO-mediated relaxation of isolated rabbit carotid arteries, which was insensitive to the removal of extracellular Ca2+ and the calmodulin antagonist calmidazolium. This phenylarsine oxide–induced vasodilatation was unaffected by genistein but abrogated by the tyrosine kinase inhibitor erbstatin A. Incubation of native or cultured endothelial cells with phenylarsine oxide resulted in a time-dependent tyrosine phosphorylation of mainly Triton X-100–insoluble (cytoskeletal) proteins, along with a parallel change in the detergent solubility of NOS III, such that the enzyme ...
Michael J. Mitchell - One of the best experts on this subject based on the ideXlab platform.
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lamin a c deficiency reduces circulating tumor cell resistance to Fluid Shear Stress
American Journal of Physiology-cell Physiology, 2015Co-Authors: Michael J. Mitchell, Celine Denais, Maxine F Chan, Zhexiao Wang, Jan Lammerding, Michael R. KingAbstract:Metastasis contributes to over 90% of cancer-related deaths and is initiated when cancer cells detach from the primary tumor, invade the basement membrane, and enter the circulation as circulating tumor cells (CTCs). While metastasis is viewed as an inefficient process with most CTCs dying within the bloodstream, it is evident that some CTCs are capable of resisting hemodynamic Shear forces to form secondary tumors in distant tissues. We hypothesized that nuclear lamins A and C (A/C) act as key structural components within CTCs necessary to resist destruction from elevated Shear forces of the bloodstream. Herein, we show that, compared with nonmalignant epithelial cells, tumor cells are resistant to elevated Fluid Shear forces in vitro that mimic those within the bloodstream, as evidenced by significant decreases in cellular apoptosis and necrosis. Knockdown of lamin A/C significantly reduced tumor cell resistance to Fluid Shear Stress, with significantly increased cell death compared with parental tumor cell and nontargeting controls. Interestingly, lamin A/C knockdown increased Shear Stress-induced tumor cell apoptosis, but did not significantly affect cellular necrosis. These data demonstrate that lamin A/C is an important structural component that enables tumor cell resistance to Fluid Shear Stress-mediated death in the bloodstream, and may thus facilitate survival and hematogenous metastasis of CTCs.
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cooperative effects of matrix stiffness and Fluid Shear Stress on endothelial cell behavior
Biophysical Journal, 2015Co-Authors: Julie C Kohn, Michael J. Mitchell, Michael R. King, Dennis W Zhou, Francois Bordeleau, Allen L Zhou, Brooke N Mason, Cynthia A ReinhartkingAbstract:Arterial hemodynamic Shear Stress and blood vessel stiffening both significantly influence the arterial endothelial cell (EC) phenotype and atherosclerosis progression, and both have been shown to signal through cell-matrix adhesions. However, the cooperative effects of Fluid Shear Stress and matrix stiffness on ECs remain unknown. To investigate these cooperative effects, we cultured bovine aortic ECs on hydrogels matching the elasticity of the intima of compliant, young, or stiff, aging arteries. The cells were then exposed to laminar Fluid Shear Stress of 12 dyn/cm2. Cells grown on more compliant matrices displayed increased elongation and tighter EC-cell junctions. Notably, cells cultured on more compliant substrates also showed decreased RhoA activation under laminar Shear Stress. Additionally, endothelial nitric oxide synthase and extracellular signal-regulated kinase phosphorylation in response to Fluid Shear Stress occurred more rapidly in ECs cultured on more compliant substrates, and nitric oxide production was enhanced. Together, our results demonstrate that a signaling cross talk between stiffness and Fluid Shear Stress exists within the vascular microenvironment, and, importantly, matrices mimicking young and healthy blood vessels can promote and augment the atheroprotective signals induced by Fluid Shear Stress. These data suggest that targeting intimal stiffening and/or the EC response to intima stiffening clinically may improve vascular health.
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Fluid Shear Stress Increases Neutrophil Activation via Platelet-Activating Factor
Biophysical Journal, 2014Co-Authors: Michael J. Mitchell, Michael R. KingAbstract:Leukocyte exposure to hemodynamic Shear forces is critical for physiological functions including initial adhesion to the endothelium, the formation of pseudopods, and migration into tissues. G-protein coupled receptors on neutrophils, which bind to chemoattractants and play a role in neutrophil chemotaxis, have been implicated as Fluid Shear Stress sensors that control neutrophil activation. Recently, exposure to physiological Fluid Shear Stresses observed in the microvasculature was shown to reduce neutrophil activation in the presence of the chemoattractant formyl-methionyl-leucyl-phenylalanine. Here, however, human neutrophil preexposure to uniform Shear Stress (0.1–2.75 dyn/cm2) in a cone-and-plate viscometer for 1–120 min was shown to increase, rather than decrease, neutrophil activation in the presence of platelet activating factor (PAF). Fluid Shear Stress exposure increased PAF-induced neutrophil activation in terms of L-selectin shedding, αMβ2 integrin activation, and morphological changes. Neutrophil activation via PAF was found to correlate with Fluid Shear Stress exposure, as neutrophil activation increased in a Shear Stress magnitude- and time-dependent manner. These results indicate that Fluid Shear Stress exposure increases neutrophil activation by PAF, and, taken together with previous observations, differentially controls how neutrophils respond to chemoattractants.
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computational and experimental models of cancer cell response to Fluid Shear Stress
Frontiers in Oncology, 2013Co-Authors: Michael J. Mitchell, Michael R. KingAbstract:It has become evident that mechanical forces play a key role in cancer metastasis, a complex series of steps that is responsible for the majority of cancer-related deaths. One such force is Fluid Shear Stress, exerted on circulating tumor cells (CTCs) by blood flow in the vascular microenvironment, and also on tumor cells exposed to slow interstitial flows in the tumor microenvironment. Computational and experimental models have the potential to elucidate metastatic cell behavior exposed to such forces. Here, we review the Fluid-generated forces that tumor cells are exposed to in the vascular and tumor microenvironments, and discuss recent computational and experimental models that have revealed mechanotransduction phenomena that may play a role in the metastatic process.
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Fluid Shear Stress sensitizes cancer cells to receptor mediated apoptosis via trimeric death receptors
New Journal of Physics, 2013Co-Authors: Michael J. Mitchell, Michael R. KingAbstract:Cancer metastasis, the process of cancer cell migration from a primary to distal location, typically leads to a poor patient prognosis. Hematogenous metastasis is initiated by intravasation of circulating tumor cells (CTCs) into the bloodstream, which are then believed to adhere to the luminal surface of the endothelium and extravasate into distal locations. Apoptotic agents such as tumor necrosis factor (TNF) apoptosis-inducing ligand (TRAIL), whether in soluble ligand form or expressed on the surface of natural killer (NK) cells, have shown promise in treating CTCs to reduce the probability of metastasis. The role of hemodynamic Shear forces in altering the cancer cell response to receptor-mediated apoptosis has not been previously investigated. Here, we report that human colon cancer COLO 205 and prostate cancer PC-3 cells exposed to a uniform Fluid Shear Stress in a cone-and-plate viscometer become sensitized to TRAIL-induced apoptosis. Shear-induced sensitization directly correlated with the application of Fluid Shear Stress, and TRAIL-induced apoptosis increased in a Fluid Shear Stress force- and time-dependent manner. In contrast, TRAIL-induced necrosis was not affected by the application Fluid Shear Stress. Interestingly, Fluid Shear Stress did not sensitize cancer cells to apoptosis when treated with doxorubicin, which also induces apoptosis in cancer cells. Caspase inhibition experiments revealed that Shear Stress-induced sensitization to TRAIL occurs via caspase-dependent apoptosis. These results suggest that physiological Fluid Shear force can modulate receptor-mediated apoptosis of cancer cells in the presence of apoptotic agents.