Endothelial Cell Proliferation Associated with Abrupt Reduction in Shear Stress Is Dependent on Reactive Oxygen Species

Milovanova, Tatyana N.; Manevich, Yefim; Haddad, Alex; Chatterjee, Shampa; Moore, Jonni S.; Fisher, Aron B.

doi:10.1089/152308604322899314

Cited by 32 publications

(65 citation statements)

References 24 publications

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“…The response to loss of shear required a preceding period of exposure to flow to reach a flow adapted state. Statically cultured cells kept for short periods under flow did not show any response to stop of flow (5,8,35). Lack or removal of flow in this model did not compromise oxygen delivery to the lung tissues or cells as normal oxygen tension was maintained during stop of flow in vivo (ventilated lung) and in vitro (continuous flow of medium through side ports) (1,5,30,46).…”

mentioning

confidence: 80%

“…In general, stop of flow involves 1) compromised oxygen delivery to tissue, and 2) alteration of the mechanical component of blood flow. We established models where stop of flow did not compromise oxygen delivery and nutrient supply; using these models we observed that abrupt cessation of flow causes ROS production via activation of endothelial cell NADPH oxidase (34,35,50). We discovered elements of the cascade, viz.…”

Section: ϫ/ϫmentioning

confidence: 99%

“…Presumably, the subset of PECAM-1 (and caveolae) that is on the luminal surface would play a major role in shear sensing compared with that at the cell contacts. ROS generated with stop of flow in vitro has been reported by us to drive cell proliferation (33)(34)(35). To understand if this cell proliferation is random or leads to formation of new vessels, we investigated the angiogenic potential of flowadapted cells subjected to stop of flow.…”

Section: ϫ/ϫmentioning

confidence: 99%

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PECAM-1 and caveolae form the mechanosensing complex necessary for NOX2 activation and angiogenic signaling with stopped flow in pulmonary endothelium

Noel

Wang

Hong

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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AB, Chatterjee S. PECAM-1 and caveolae form the mechanosensing complex necessary for NOX2 activation and angiogenic signaling with stopped flow in pulmonary endothelium. Am J Physiol Lung Cell Mol Physiol 305: L805-L818, 2013. First published September 27, 2013 doi:10.1152/ajplung.00123.2013.-We showed that stop of flow triggers a mechanosignaling cascade that leads to the generation of reactive oxygen species (ROS); however, a mechanosensor coupled to the cytoskeleton that could potentially transduce flow stimulus has not been identified. We showed a role for KATP channel, caveolae (caveolin-1), and NADPH oxidase 2 (NOX2) in ROS production with stop of flow. Based on reports of a mechanosensory complex that includes platelet endothelial cell adhesion molecule-1 (PECAM-1) and initiates signaling with mechanical force, we hypothesized that PECAM-1 could serve as a mechanosensor in sensing disruption of flow. Using lungs in situ, we observed that ROS production with stop of flow was significantly reduced in PECAM-1 Ϫ/Ϫ lungs compared with lungs from wild-type (WT) mice. Lack of PECAM-1 did not affect NOX2 activation machinery or the caveolin-1 expression or caveolae number in the pulmonary endothelium. Stop of flow in vitro triggered an increase in angiogenic potential of WT pulmonary microvascular endothelial cells (PMVEC) but not of PECAM-1 Ϫ/Ϫ PMVEC. Obstruction of flow in lungs in vivo showed that the neutrophil infiltration as observed in WT mice was significantly lowered in PECAM-1 Ϫ/Ϫ mice. With stop of flow, WT lungs showed higher expression of the angiogenic marker VEGF compared with untreated (sham) and PECAM-1 Ϫ/Ϫ lungs. Thus PECAM-1 (and caveolae) are parts of the mechanosensing machinery that generates superoxide with loss of shear; the resultant ROS potentially drives neutrophil influx and acts as an angiogenic signal. mechanotransduction; stop of flow; pulmonary endothelium; PECAM; K atp (Kir6.2) channel; NOX2; angiogenic potential CELLS SENSE THE PHYSICAL STIMULUS in their environment and translate these physical forces into biochemical signals (20, 37). Sensing and responding to a physical force require specialized structures and machinery that can engage in signal transduction (12,23,42).In the vascular system, with a highly distributed network of blood vessels, mechanical forces arising from blood flow initiate signaling that helps maintain vascular structure and function. Indeed, shear associated with blood flow is sensed by the endothelium and the resultant signaling regulates normal vascular physiology (such as embryonic morphogenesis and organization of the vascular tree) while irregular or abnormal shear can lead to vascular dysfunction and disease (19,27). Thus the mechanosignaling that accompanies various shear profiles and patterns, regular or aberrant, governs susceptibility to atherosclerosis, by inducing athero-protective or atheroprone phenotypes in endothelial cells (10,22). It thus becomes important to understand the link among the mechanical force, the shear sensing machinery and...

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mentioning

confidence: 80%

Section: ϫ/ϫmentioning

confidence: 99%

Section: ϫ/ϫmentioning

confidence: 99%

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PECAM-1 and caveolae form the mechanosensing complex necessary for NOX2 activation and angiogenic signaling with stopped flow in pulmonary endothelium

Noel

Wang

Hong

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Recent studies have demonstrated that the NOX family of enzymes consists of seven widely distributed members (86). The enzyme found in PMN and now called NOX2 also is present in a variety of cell types including microvascular endothelium, where it plays an important role in cellular homeostasis (7,21,25,73,74,115). In our models of altered shear stress, endothelial NADPH oxidase clearly is the source of ROS with ischemia since use of inhibitors of NOX2 activation as well as lungs and cells from NOX2-null mice abolished the effect.…”

Section: Ros Generation: Mechanism For Linkage To Altered Shear Stressmentioning

confidence: 99%

Shear stress-related mechanosignaling with lung ischemia: lessons from basic research can inform lung transplantation

Chatterjee

Nieman

Christie

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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Chatterjee S, Nieman GF, Christie JD, Fisher AB. Shear stress-related mechanosignaling with lung ischemia: lessons from basic research can inform lung transplantation. Am J Physiol Lung Cell Mol Physiol 307: L668 -L680, 2014. First published September 19, 2014 doi:10.1152/ajplung.00198.2014.-Cessation of blood flow represents a physical event that is sensed by the pulmonary endothelium leading to a signaling cascade that has been termed "mechanotransduction." This paradigm has clinical relevance for conditions such as pulmonary embolism, lung bypass surgery, and organ procurement and storage during lung transplantation. On the basis of our findings with stop of flow, we postulate that normal blood flow is "sensed" by the endothelium by virtue of its location at the interface of the blood and vessel wall and that this signal is necessary to maintain the endothelial cell membrane potential. Stop of flow is sensed by a "mechanosome" consisting of PECAM-VEGF receptor-VE cadherin that is located in the endothelial cell caveolae. Activation of the mechanosome results in endothelial cell membrane depolarization that in turn leads to activation of NADPH oxidase (NOX2) to generate reactive oxygen species (ROS). Endothelial depolarization additionally results in opening of T-type voltage-gated Ca 2ϩ channels, increased intracellular Ca 2ϩ, and activation of nitric oxide (NO) synthase with resultant generation of NO. Increased NO causes vasodilatation whereas ROS provide a signal for neovascularization; however, with lung transplantation overproduction of ROS and NO can cause oxidative injury and/or activation of proteins that drive inflammation and cell death. Understanding the key events in the mechanosignaling cascade has important lessons for the design of strategies or interventions that may reduce injury during storage of donor lungs with the goal to increase the availability of lungs suitable for donation and thus improving access to lung transplantation. lung ischemia; ischemia-reperfusion; lung transplantation; mechanotransduction; reactive oxygen species; K ATP channel; NADPH oxidase; lung perfusion and storage; EVLP THE RELATED TERMS mechanosensing, mechanosignaling, and mechanotransduction refer to the sensing of physical forces by cells and their translation into a biochemical response, analogous to the processes termed chemotransduction. Among the various physical forces to which cells in vivo are constantly exposed, mechanical stimuli associated with blood flow are particularly important. Indeed, fluid shear stress and distending pressure that act on the vessel wall play a major role in vascular homeostasis. The vascular endothelium, by virtue of its location, serves as an interface between the blood and tissue for hemodynamic changes. Recent work demonstrates that the endothelium senses and integrates hemodynamic stimuli including shear to effect maintenance of vascular function and possibly modulate the onset of vascular disease. The currently accepted paradigm is that "sensing" of a change (either increa...

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“…3). O 2 ·Ϫ serves as a signal for endothelial cell proliferation, perhaps, teleologically, representing an attempt to restore pulmonary blood flow (62). Thus ROS mediatedsignaling appears to play a key role in the physiological response to altered shear stress associated with lung ischemia (10).…”

Section: Lung Ischemiamentioning

confidence: 99%

The serpentine path to a novel mechanism-based inhibitor of acute inflammatory lung injury

Fisher

2014

Journal of Applied Physiology

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Endothelial Cell Proliferation Associated with Abrupt Reduction in Shear Stress Is Dependent on Reactive Oxygen Species

Cited by 32 publications

References 24 publications

PECAM-1 and caveolae form the mechanosensing complex necessary for NOX2 activation and angiogenic signaling with stopped flow in pulmonary endothelium

PECAM-1 and caveolae form the mechanosensing complex necessary for NOX2 activation and angiogenic signaling with stopped flow in pulmonary endothelium

Shear stress-related mechanosignaling with lung ischemia: lessons from basic research can inform lung transplantation

The serpentine path to a novel mechanism-based inhibitor of acute inflammatory lung injury

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