A mechanism for heterogeneous endothelial responses to flow in vivo and in vitro

Davies, Peter; Mundel, Trevor; Barbee, Kenneth A.

doi:10.1016/0021-9290(95)00102-6

Cited by 125 publications

(44 citation statements)

References 18 publications

(44 reference statements)

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“…These mechanical stimuli play an important role in the regulation of various aspects of vascular EC function, including cell proliferation, changes in cell morphology, cell migration, NO production, Ca 2ϩ influx, and gene expression, and they are implicated in vasculogenesis, angiogenesis, and atherosclerosis (1)(2)(3)(4). ECs are equipped with mechanotransducers, such as vascular endothelial growth factor receptor 2 (VEGFR2), integrins, VE-cadherin, and platelet/ endothelial adhesion molecule 1 (PECAM1), which sense mechanical forces and convert them into biochemical signaling cascades (1,3,4).…”

Section: Our Results Suggest That the Polarized Redistribution Of Ve-mentioning

confidence: 99%

Shear Stress-induced Redistribution of Vascular Endothelial-Protein-tyrosine Phosphatase (VE-PTP) in Endothelial Cells and Its Role in Cell Elongation

Mantilidewi

Murata

Mori

et al. 2014

Journal of Biological Chemistry

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Background: Mechanical stimuli such as shear stress regulate endothelial cell (EC) function. Results: Shear stress induced a rapid redistribution of the protein-tyrosine phosphatase VE-PTP in ECs, and knockdown of VE-PTP prevented shear stress-induced EC elongation. Conclusion: VE-PTP is important for shear stress-induced changes in EC morphology. Significance: VE-PTP is implicated in regulation of EC function by shear stress.

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Section: Our Results Suggest That the Polarized Redistribution Of Ve-mentioning

confidence: 99%

Shear Stress-induced Redistribution of Vascular Endothelial-Protein-tyrosine Phosphatase (VE-PTP) in Endothelial Cells and Its Role in Cell Elongation

Mantilidewi

Murata

Mori

et al. 2014

Journal of Biological Chemistry

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“…The mechanical stress generated on the EC layer due to this flow is an important extrinsic factor capable of modifying vessel barrier properties through alteration of the inter-endothelial junctions and the EC-extracellular matrix interactions. [20][21][22][23] It can also activate intracellular signaling events, altering barrier properties like increased intracellular Ca 2þ levels and the generation of inositol trisphosphate, [24][25][26] activation of Rac, 27,28 RhoA-dependent reorganization of the actin cytoskeleton, 21,22,29 and b 1 -integrin-dependent increases in caveolin-1 phosphorylation. 21 Therefore, integration of in vivo levels of flow with the EC culture is important in limiting the chances of the cell monolayer undergoing phenotypic drifts and no longer reflecting in situ characteristics.…”

Section: Introductionmentioning

confidence: 99%

Characterization of vascular permeability using a biomimetic microfluidic blood vessel model

et al. 2017

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The inflammatory response in endothelial cells (ECs) leads to an increase in vascular permeability through the formation of gaps. However, the dynamic nature of vascular permeability and external factors involved is still elusive. In this work, we use a biomimetic blood vessel (BBV) microfluidic model to measure in real-time the change in permeability of the EC layer under culture in physiologically relevant flow conditions. This platform studies the dynamics and characterizes vascular permeability when the EC layer is triggered with an inflammatory agent using tracer molecules of three different sizes, and the results are compared to a transwell insert study. We also apply an analytical model to compare the permeability data from the different tracer molecules to understand the physiological and bio-transport significance of endothelial permeability based on the molecule of interest. A computational model of the BBV model is also built to understand the factors influencing transport of molecules of different sizes under flow. The endothelial monolayer cultured under flow in the BBV model was treated with thrombin, a serine protease that induces a rapid and reversible increase in endothelium permeability. On analysis of permeability data, it is found that the transport characteristics for fluorescein isothiocyanate (FITC) dye and FITC Dextran 4k Da molecules are similar in both BBV and transwell models, but FITC Dextran 70k Da molecules show increased permeability in the BBV model as convection flow (Peclet number > 1) influences the molecule transport in the BBV model. We also calculated from permeability data the relative increase in intercellular gap area during thrombin treatment for ECs in the BBV and transwell insert models to be between 12% and 15%. This relative increase was found to be within range of what we quantified from F-actin stained EC layer images. The work highlights the importance of incorporating flow in in vitro vascular models, especially in studies involving transport of large size objects such as antibodies, proteins, nano/micro particles, and cells. Published by AIP Publishing.

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“…5 Indeed, as Ingber 18 has suggested, the entire cytoskeleton may participate in what he called a tensegrity-based stimulus-response coupling, which dynamically integrates externally applied stresses, extracellular matrix attachments, and internal strains into adaptive biological responses. Given that the endothelial cell cytoskeleton and focal adhesion complexes can actively be remodeled in response to applied forces 5 and that there are regional differences in the magnitude of shear stresses across the surface of a given endothelial cell (reflecting details of its surface topography), 19,20 the potential for significant heterogeneity in responsiveness among cells within a uniform flow field also exists. Interestingly, although this is a relatively complex model for biomechanical transduction, considerable observational data support it.…”

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confidence: 99%

Vascular Endothelium, Hemodynamic Forces, and Atherogenesis

Gimbrone

1999

The American Journal of Pathology

195

119

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Intimal lipid accumulation, hyperplasia, and scarring are stigmata of atherosclerotic vascular disease, whose major complications-myocardial and cerebral ischemia and infarction-continue to be major health problems in developed nations. 1 This insidiously progressive disease typically spans decades, but can reach a clinical horizon in a matter of minutes due to critical changes in a given atherosclerotic plaque that result in localized but lifethreatening thrombosis. Epidemiological studies have established that hypercholesterolemia is an important risk factor in this disease process, and lipid-lowering drugs have been proven to have clinical efficacy. Experimental animals that are fed lipid-rich diets to elevate their plasma cholesterol levels also can develop atherosclerotic-like lesions, as do animals with naturally occurring or genetically engineered mutations that result in altered cholesterol metabolism. However, regardless of a given patient's risk factor profile, species of animal model, or type of natural or engineered genetic alteration, the early, lipid-rich lesions of atherosclerosis show a markedly nonrandom pattern of distribution within the arterial vasculature. Atherosclerotic lesions typically develop in the vicinity of branch points and areas of major curvature. These arterial geometries are associated with blood flow disturbances such as nonuniform laminar flow with boundary layer separation, complex secondary flows with flow reversal and dynamic stagnation points, and resultant temporal and spatial gradients in wall shear stresses. In contrast to these atherosclerosis-prone areas, unbranched, tubular arterial geometries, which are associated with a more uniformly laminar flow profile, characteristically are relatively atherosclerosis-resistant, at least in the early phases of the disease. This strikingly localized pattern of lesion formation, even in the face of systemic risk factors such as elevated plasma cholesterol, has intrigued experimental pathologists and fluid mechanical engineers alike for decades, and has motivated the search for a mechanistic link between hemodynamic forces and atherogenesis.In this issue of The American Journal of Pathology, Zand and coworkers 2 describe a novel experimental model system for creating flow disturbances in the aorta of the rat that have significant effects on the pattern of intimal lipid deposition induced by chronic dietary hypercholesterolemia. Surgical insertion of a hemispherical glass plug into the aortic lumen, through the ostium of a severed renal artery, created a significant stenosis (greater than 50% cross-sectional area reduction) without causing any compression of the adjacent aortic wall, as typically occurs in other models involving an externally applied ligature or metal clip. This model thus accomplishes two useful things: it reliably creates an altered vascular geometry designed to induce well characterized intraluminal flow perturbations while it minimizes the confounding issue of concomitant (and often less well characterized) ch...

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A mechanism for heterogeneous endothelial responses to flow in vivo and in vitro

Cited by 125 publications

References 18 publications

Shear Stress-induced Redistribution of Vascular Endothelial-Protein-tyrosine Phosphatase (VE-PTP) in Endothelial Cells and Its Role in Cell Elongation

Shear Stress-induced Redistribution of Vascular Endothelial-Protein-tyrosine Phosphatase (VE-PTP) in Endothelial Cells and Its Role in Cell Elongation

Characterization of vascular permeability using a biomimetic microfluidic blood vessel model

Vascular Endothelium, Hemodynamic Forces, and Atherogenesis

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