A Microfluidic System for Studying the Effects of Disturbed Flow on Endothelial Cells

Tovar-Lopez, Francisco J.; Thurgood, Peter; Gilliam, Christopher; Nguyen, Ngan; Pirogova, Elena; Khoshmanesh, Khashayar; Baratchi, Sara

doi:10.3389/fbioe.2019.00081

Cited by 85 publications

(68 citation statements)

References 44 publications

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“…The main obstacle in trying to answer these questions from the available literature, is that up to this point, turbulent flow (referred to in most of the literature as disturbed flow) is considered to be pathologic as opposed to laminar flow 84,85 . Moreover, on most studies that discussed the differences between laminar and turbulent flow regimes on endothelial mechanobiology, both laminar and turbulent flows were at different WSS values 8,86,87 .…”

Section: Discussionmentioning

confidence: 99%

Physiologic blood flow is turbulent

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Tupin

Rashad

et al. 2020

Sci Rep

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Contemporary paradigm of peripheral and intracranial vascular hemodynamics considers physiologic blood flow to be laminar. Transition to turbulence is considered as a driving factor for numerous diseases such as atherosclerosis, stenosis and aneurysm. Recently, turbulent flow patterns were detected in intracranial aneurysm at Reynolds number below 400 both in vitro and in silico. Blood flow is multiharmonic with considerable frequency spectra and its transition to turbulence cannot be characterized by the current transition theory of monoharmonic pulsatile flow. Thus, we decided to explore the origins of such long-standing assumption of physiologic blood flow laminarity. Here, we hypothesize that the inherited dynamics of blood flow in main arteries dictate the existence of turbulence in physiologic conditions. To illustrate our hypothesis, we have used methods and tools from chaos theory, hydrodynamic stability theory and fluid dynamics to explore the existence of turbulence in physiologic blood flow. Our investigation shows that blood flow, both as described by the Navier–Stokes equation and in vivo, exhibits three major characteristics of turbulence. Womersley’s exact solution of the Navier–Stokes equation has been used with the flow waveforms from HaeMod database, to offer reproducible evidence for our findings, as well as evidence from Doppler ultrasound measurements from healthy volunteers who are some of the authors. We evidently show that physiologic blood flow is: (1) sensitive to initial conditions, (2) in global hydrodynamic instability and (3) undergoes kinetic energy cascade of non-Kolmogorov type. We propose a novel modification of the theory of vascular hemodynamics that calls for rethinking the hemodynamic–biologic links that govern physiologic and pathologic processes.

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Section: Discussionmentioning

confidence: 99%

Physiologic blood flow is turbulent

Saqr

Tupin

Rashad

et al. 2020

Sci Rep

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“…Thus, the protective effects of GPR81 against oxidative stress, inflammation, and attachment of monocytes to endothelial cells are likely to be robustly suppressed in atherosclerosis‐prone sites, such as bifurcations and other areas of the vasculature exposed to OSS patterns. Recent research has demonstrated the important role of the activation of such mechanotransduction pathways in endothelial cells . The cessation of blood flow, aberrant flow patterns, shear stress, and OSS were shown to induce redox signaling, inflammatory response, and a shift in endothelial cells toward a pathological phenotype, thereby promoting endothelial dysfunction .…”

Section: Discussionmentioning

confidence: 99%

Activation of GPR81 by lactate inhibits oscillatory shear stress‐induced endothelial inflammation by activating the expression of KLF2

et al. 2019

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Atherosclerosis is a common and deadly cardiovascular disease with extremely high prevalence. Areas of the vasculature exposed to oscillatory shear stress (OSS) or disturbed blood flow are particularly prone to the development of atherosclerotic lesions. In part, various mechanosensitive receptors on the surface of endothelial cells play a role in regulating the ability of the vasculature to cope with variations in blood flow patterns. However, the exact mechanisms behind flow-mediated endothelial responses remain poorly understood. Along with the development of highly specific receptor agonists, the class of G coupled-protein receptors has been receiving increasing attention as potential therapeutic targets. G coupled-protein receptor 81 (GPR81), also known as hydroxycarboxylic acid receptor 1 (HCA 1 ), is activated by lactate, its endogenous ligand. In the present study, we show for the first time that expression of GPR81 is significantly downregulated in response to OSS in endothelial cells and that activation of GPR81 using physiologically relevant doses of lactate can rescue OSS-induced reduced GPR81 expression. Importantly, our findings demonstrate that activation of GPR81 can exert valuable atheroprotective effects in endothelial cells exposed to OSS by reducing oxidative stress and significantly downregulating the expression of inflammatory cytokines including interleukin (IL)-6, IL-8, monocyte chemoattractant protein (MCP)-1, and high mobility group box 1 (HMGB1). We also show that activation of GPR81 can potentially prevent the attachment of monocytes to the endothelium by suppressing OSS-induced secretion of vascular cellular adhesion molecule (VCAM)-1 and endothelial-selectin (E-selectin). Finally, we show that activation of GPR81 can rescue OSS-induced reduced expression of the key atheroprotective transcription factor Kruppel-like factor 2 (KLF2), which is mediated through the extracellularregulated kinase 5 (ERK5) pathway. These findings demonstrate a potential Abbreviations: ECL, electrochemiluminescence; E-selectin, endothelial-selectin; ELISA, Enzyme-linked immunosorbent assay; ERK5, extracellularregulated kinase 5; FBS, fetal bovine serum; GPR81, G coupled-protein receptor 81; GPCRs, G protein-coupled receptors; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HMGB1, high mobility group box 1; HSS, high shear stress; HUVECs, human umbilical vascular endothelial cells; HCA 1 , hydroxycarboxylic acid receptor 1; IL-6, interleukin; KLF2, Kruppel-like factor 2; MAPK, mitogen-activated protein kinase; MCP-1, monocyte chemoattractant protein; OSS, oscillatory shear stress; PAK1, p21-activated kinase 1; PVDF, polyvinylidene fluoride; ROS, reactive oxygen species; RT-PCR, reverse transcription PCR; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis; VCAM-1, vascular cellular adhesion molecule.

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“…PDMS-hydrogel hybrid devices can incorporate branching and bifurcating regions of special interest for capillary splitting and other remodeling events due to the different flow patterns occurring at these sites. This type of devices have recently been used to produce impinging bifurcating fluid flow, laminar shear stress and transvascular fluid flow (Akbari et al, 2018) and also controllable disturbed flow patterns for the study of its effects on actin stress fiber and endothelial cell orientation (Tovar-Lopez et al, 2019). But how exactly does the direction, slope and average magnitude of shear stress gradients affect endothelial cell biological and molecular responses needs still to be understood.…”

Section: In Vitro Systems For Analysis Of Microvascular Remodeling Unmentioning

confidence: 99%