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Trends in Molecular Medicine

Vascular endothelial responses to altered shear stress: Pathologic implications for atherosclerosis

Jeng-Jiann Chiu Division of Medical Engineering Research, National Health Research Institutes, Taiwan, Republic of China
,
Shunichi Usami Department of Bioengineering and Whitaker Institute of Biomedical Engineering, University of California, San Diego, La Jolla, CA, USA
&
Shu Chien Department of Bioengineering and Whitaker Institute of Biomedical Engineering, University of California, San Diego, La Jolla, CA, USA; Department of Medicine, University of California, San Diego, La Jolla, CA, USA
, PhD , MD
Pages 19-28
Received 07 Mar 2008
Published online: 08 Jul 2009

Trends in Molecular Medicine

Vascular endothelial responses to altered shear stress: Pathologic implications for atherosclerosis

Abstract

Atherosclerosis preferentially develops at branches and curvatures of the arterial tree, where blood flow is disturbed from a laminar pattern, and wall shear stress is non-uniform and has an irregular distribution. Vascular endothelial cells (ECs), which form an interface between the flowing blood and the vessel wall, are exposed to blood flow-induced shear stress. There is increasing evidence suggesting that laminar blood flow and sustained high shear stress modulate the expression of EC genes and proteins that function to protect against atherosclerosis; in contrast, disturbed blood flow and the associated low and reciprocating shear stress upregulate proatherosclerotic genes and proteins that promote development of atherosclerosis. Understanding of the effects of shear stress on ECs will provide mechanistic insights into its role in the pathogenesis of atherosclerosis. The aim of this review article is to summarize current findings on the effects of shear stress on ECs, in terms of their signal transduction, gene expression, structure, and function. These endothelial cellular responses have important relevance to understanding the pathophysiological effects of altered shear stress associated with atherosclerosis and thrombosis and their complications.

Introduction

Atherosclerosis develops preferentially in regions of the arterial tree where non-uniform and irregular distribution of wall shear stress is generated by complex patterns of blood flow 1–4. There is a considerable amount of evidence that hemodynamic characteristics determine the location of lesions and contribute to the pathogenesis of atherosclerosis 5–7. Vascular endothelial cells (ECs), which form the interface between the flowing blood and the vessel wall, are subjected to various chemical and mechanical stimuli. In addition to serving as a permeability barrier, ECs perform many important functions, such as the production, secretion, and metabolism of biochemical substances, and their dysfunction plays important roles in atherogenesis 8–14. Recent evidence suggests that laminar blood flow (i.e. streamlined blood flow where viscous forces are predominant over inertial forces) and sustained high shear stress in the straight part of the artery downregulate atherogenesis-related genes (e.g. monocyte chemotactic protein-1 (MCP-1)) and upregulate antioxidant and growth arrest genes in ECs 11. In contrast, disturbed flow (i.e. non-uniform and irregular flow and recirculation) and the associated low and reciprocating shear stress at branch points of the arterial tree cause sustained induction of MCP-1 in ECs and enhance monocyte infiltration into the arterial wall 11. These findings provide a cellular and molecular basis for the explanation of the preferential localization of atherosclerotic lesions at regions of disturbed flow with altered shear stress, such as the arterial branch points and curvatures. Elucidation of the effects of different flow patterns and shear stresses on ECs will provide the molecular and cellular bases for understanding the role of hemodynamic factors in the pathogenesis of atherosclerosis. This article provides a brief summary of the current knowledge on the effects of different flow patterns and shear stresses on ECs, in terms of their signal transduction, gene expression, structure, and function. Understanding of these EC responses will provide insight into the roles of disturbed shear stress in regulating the physiology and pathobiology of the vessel wall through complex molecular mechanisms that promote atherogenesis.

Key messages

  • Laminar blood flow and sustained high shear stress seen in the straight part of the arterial tree modulate the expression of genes and proteins in endothelial cells to protect against atherosclerosis.

  • Disturbed blood flow and reciprocating shear stress with little forward direction seen in vascular branch points and other regions of complex flow cause the expression of atherogenic genes and proteins to predispose these areas to atherosclerosis.

  • These endothelial responses to different flow patterns have important relevance to understanding the pathophysiological roles of altered shear stress in atherosclerosis and thrombosis and their complications.

Fluid shear stress and the focal origin of atherosclerosis

Blood vessels are constantly exposed to various types of hemodynamic forces (including fluid shear stress, cyclic stretch, and hydrostatic pressure) induced by the pulsatile blood flow and pressure (Figure 1). As a monolayer in direct contact with the flowing blood, ECs bear most of the wall shear stress, which is the component of frictional forces arising from the blood flow and acting parallel to the vessel luminal surface 10, 15, 16. The magnitude of shear stress can be estimated in straight vessels as being proportional to the blood flow and viscosity and inversely proportional to the third power of the internal radius of vessel 5, 16. Experimental measurements using different methods have shown that the magnitudes of shear stress range from 0.1 to 0.6 N/m2 in the venous system and from 1 to 7 N/m2 in the arterial vessels 5, 17. In-vivo observations indicate that shear stress can play critical roles in vascular homeostasis and remodeling 18, 19. For example, alteration in shear stress in systemic arterial hypertension can modulate vascular tone and result in the chronic process of vascular remodeling 12, 19. Increases in blood flow would cause an initial increase in shear stress, which induces an expansion of the internal radius of the vessel to maintain the mean shear stress at the baseline level 18, 20. Conversely, decreased shear stress resulting from lower blood flow or blood viscosity 21 induces a decrease in internal vessel radius 19. This stabilizing control of shear stress requires an intact, functional endothelium and its ability to undergo adaptive adjustments in structure and function in response to changes in shear stress 19. The net effect of these endothelium-mediated compensatory responses is the maintenance of mean shear stress of the arterial system at approximately 1.5 to 2 N/m2 5, 20.

Figure 1.  Schematic diagram showing the generation of shear stress (parallel to the endothelial cell surface) by blood flow and the generation of normal stress (perpendicular to the endothelial cell surface) and circumferential stretch due to the action of pressure. Reproduced with permission from Chien 11.

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The atherosclerotic lesions are preferentially located at the outer walls of the arterial branches and curvatures, where the local flow is disturbed (e.g. non-uniform and irregular oscillation and recirculation) 1–4. In these geometrically predisposed regions, fluid shear stress on the vessel wall is significantly lower in magnitude and exhibits directional changes with flow separation and reattachment. Direct measurements and fluid mechanical analyses of models of these lesion-prone areas have revealed that shear stress are on the order of ±0.4 N/m2 in these areas with a very small net magnitude that is much lower than the values of >1.2 N/m2 in the lesion-free areas 5. The sparing of regions with a large net flow and the proneness for lesion formation in regions of disturbed flow suggest that physiological or high levels of shear stress play protective roles against atherosclerosis, whereas complex patterns of blood flow with altered shear stress and little net direction may act as detrimental mechanical stimuli contributing to atherogenesis 5–7, 14.

Shear stress acts as a modulator of endothelial phenotype

In-vitro and in-vivo studies have suggested that shear stress acts as a critical modulator of endothelial phenotype. Evidence of direct effects of shear stress on endothelial structure and function has been obtained primarily from in-vitro studies using cultured ECs in the flow channel, which have facilitated the investigation of cellular responses to different types of shear flow (e.g. laminar, pulsatile, disturbed, or reciprocating flow) under controlled experimental conditions. One of the earliest observations on the effects of shear stress on ECs is a striking reorganization of EC morphology in response to sustained laminar shear flow 22. In response to sufficient magnitude and duration of steady laminar shear stress, ECs become aligned and elongated in the direction of flow, with a significant alteration in cytoskeletal architecture. This observation on EC morphological responses induced by flow in vitro recapitulates many of the morphological features that have been described for ECs in straight parts of the arterial tree in vivo 23. Furthermore, sustained laminar shear stress has been shown to activate signaling pathways that reduce the number of cells entering the cell cycle, with the majority of cells being arrested in the G0 or G1 phase 24. EC turnover is accelerated in areas with disturbed flow with low shear stress 25, probably due to the release of p21 suppression of cyclin-dependent kinase activity via G0/G1-S transition 26, 27. Such accelerated cell turnover would lead to an enhanced macromolecular permeability and contribute to the increases in lipid uptake at regions of disturbed flow 28.

Effects of shear stress on EC signaling and gene and protein expressions

Mechanosensing of shear stress

There are several mechanisms by which ECs sense shear stress acting on their luminal sides 10, 11. Following the initial mechanosensing, EC surfaces and membranes may be deformed, ions may be translocated, local biochemical responses and downstream intracellular signaling pathways may be activated, and gene and protein expressions may then be modulated, to result in consequent modifications of EC structure and function. Work done in our laboratory has shown that the vascular endothelial growth factor receptor (which is a receptor tyrosine kinase (RTK)) on the luminal side of ECs 29 and integrins on the abluminal side 30 can serve as mechanosensors (Figure 2). Integrin-extracellular matrix (ECM) interactions are implicated in mechanotransduction by their modulation of downstream pathways that have anti- or proatherogenic activities 31. In addition, the glycocalyx is postulated to be disrupted by shear stress, leading to modifications of ion channels and membrane receptors 32. Other potential EC membrane mechanosensors are G proteins and G-protein-coupled receptors (GPCRs), caveolae, platelet-endothelial cell adhesion molecule-1 (PECAM-1), gap junctions, and membrane lipids 10, 11. Using 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiI) and the technique of fluorescence recovery after photobleaching, Butler et al. 33, 34 found that shear stress increases membrane fluidity, preferentially on the upstream side of the ECs. This increase in fluidity may facilitate the lateral mobility of membrane proteins and enhance their interactions, e.g. oligomerization.

Figure 2.  Schematic diagram showing the action of shear stress on potential sensors in endothelial cells (ECs), including receptor tyrosine kinases (RTK), G protein-coupled receptor (GPCR), ion channels, junction proteins, and integrins, as well as membrane lipids and glycocalyx. These mechanosensors act through adaptor molecules (represented by the two dotted circles) to activate upstream signaling molecules such as Ras, which then activate the mitogen-activated protein (MAP) kinase pathways, including ERK and JNK, and then the transcription factors (e.g. activator protein-1 (AP-1)) for gene expression (e.g. monocyte chemotactic protein-1 (MCP-1)). Arrows to the left of ERK and JNK are used to represent the phosphorylation cascade that involves the sequential phosphorylation of protein kinases one after the other. Various mechanotransduction pathways are used to modulate the expression of different genes. Also shown are the small GTPase Rho and its downstream molecules Rho kinase (ROCK) and mDia, which are stimulatory to actin. It is also possible for mechanical signals to be perceived by the cytoskeleton, including actin, to modulate gene expression, e.g. the interactions (direct or indirect) between actin and JNK. This diagram illustrates that mechanotransduction involves the interplay among many mechanosensors, signaling molecules, and genes, all of which form complex networks to modulate EC structure and function. Reproduced with permission from Chien 11.

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The endothelial cytoskeleton is also proposed to play a central role in mechanotransduction of shear stress, with direct participation of structural cytoskeletal fibers as well as involvement of cytoskeletal-associated structures such as focal adhesions and adherens junctions 35–37. Mechanotransduction in response to shear stress can be mediated by conformational changes in the cell cytoskeleton and/or in the cell-cell and the cell-ECM adhesion complexes. Shear stress activates Rho family GTPases (a large family of hydrolase enzymes that can bind and hydrolyze GTP (guanosine-5′-triphosphate), e.g. Rac), enhances formation of stress fibers and focal adhesions, and increases EC-ECM adhesion strength, all of which may contribute to the increase in EC migration velocity under shear 38, 39. Our results indicate that EC migration is governed by a balance of forces, including the externally applied shear force, the EC-ECM adhesion force, and the intracellular locomotive forces resulting from mechanochemical transduction 11.

Effects of shear stress on MCP-1 expression in ECs

The activation of mechanosensors by shear stress leads to the triggering of phosphorylation cascades of signaling molecules and the consequent modulation of gene expression. For example, the Ras-MAPKs (mitogen-activated protein kinases) pathway mediates the shear stress induction of MCP-1 gene and protein in ECs 11, 40, 41. The activation of MAPKs entails the phosphorylation of a series of serine-threonine protein kinases (Figure 2), with Ras serving as an upstream molecule and extracellular signal-regulated kinase (ERK), c-Jun-NH2-terminal kinase (JNK), and p38 as three key downstream MAPK molecules. A sustained application of laminar shear stress results in only transient activation of the Ras-MAPK signaling pathway and transient MCP-1 expression followed by its downregulation. When ECs are subjected to complex flow patterns with altered shear stress simulating those seen at branch points, the downregulation of MCP-1 in response to sustained flow does not occur. Thus, there is a sustained activation of genes such as MCP-1 in areas with complex flow patterns, especially the flow reattachment area, which has a low shear stress and a high shear stress gradient. The induction of MCP-1 expression by oxidative stress has also been shown to be attenuated by pulsatile shear stress with a positive mean flow rate and augmented by reciprocating shear stress with little net flow 42. The functional consequence of the downregulation in response to sustained laminar shear stress is a suppression of monocyte attraction into the vessel wall and is thus atheroprotective.

Effects of different flow patterns and shear stresses on EC signaling and gene and protein expressions

In addition to MCP-1, in-vitro studies using parallel-plate flow chamber or cone-and-plate viscometer have identified a number of pathophysiologically relevant genes, whose expression is modulated by different types of shear stress. For example, reciprocating flow (0.02±0.5 N/m2) has been shown to induce the expression of molecules involved in atherogenesis, including the adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) 43 and E-selectin 44, and the vasoconstrictor endothelin-1 (ET-1) 45; in contrast, steady shear stress with a significant forward direction has little effect on E-selectin and ICAM-1 expression 46, 47 and causes a downregulation of ET-1 and vascular cell adhesion molecule-1 (VCAM-1) 48–50. The expression of the proinflammatory gene bone morphogenic protein-4 (BMP-4) in ECs increases in response to reciprocating flow (0±0.5 N/m2) but decreases following steady laminar flow (1.5 N/m2) 43. Exposure of ECs to sustained laminar shear stress increases the expression of Krüppel-like factor-2 (KLF-2) that plays anti-inflammatory roles 51, 52. In contrast, there is virtually no KLF-2 expression in ECs exposed to reciprocating shear stress 52. Using an orbital model that creates a laminar high shear stress in the periphery and a disturbed low shear stress in the center of the well, Yun et al. 53 and Dardik et al. 54 demonstrated that exposing ECs to a disturbed flow with low shear led to increases in their ICAM-1 and E-selectin expressions, Sp1 phosphorylation, platelet-derived growth factor (PDGF)-BB and interleukin (IL)-1α secretions, EC proliferation and apoptosis, as compared with the cells exposed to a laminar high shear. Reciprocating flow (0.02±0.5 N/m2) also causes a sustained elevation of oxidative stress in ECs by continued increases of intracellular superoxide, reduced nicotinamide adenine dinucleotide (NADH) oxidase activity, and heme oxygenase-1 (HO-1) mRNA; whereas steady flow causes only a transient induction of reactive oxygen species (ROS), NADH oxidase, and HO-1 55. The sustained superoxide production induced by reciprocating flow (0±0.5 and 0±1.5 N/m2) is dependent on p47phox (one of the major cytosolic components of NADH/(reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex) 56 and xanthine oxidase 57, and is contributed by the p22phox gene induction 58. Hwang et al. 59 also showed that reciprocating flow (0±0.3 N/m2) causes the upregulation of gp91phox and NOX4 expression (major membrane-associated components of NADH/NADPH oxidase complex), and that pulsatile flow (2.5±0.3 N/m2) decreases the expression of these two genes. These gene expression patterns in response to reciprocating and pulsatile flows correlate well with EC superoxide production, low-density lipoprotein (LDL) oxidation, MCP-1 expression, and monocyte-EC binding 56. Furthermore, steady laminar flow upregulates endothelial nitric oxide synthase (eNOS) and induces productions of nitric oxide (NO) and prostacyclin 60–63, which are presumably antiatherogenic, whereas reciprocating flow does not cause the induction of eNOS and productions of NO and prostacyclin 45, 64, 65. Several studies have demonstrated a decreased NO bioavailability in the early stage of atherosclerosis as a possible consequence of inactivation by superoxide anion 65. Conklin et al. 66 demonstrated that low shear stress results in significant increases in EC mRNA and protein expressions of vascular endothelial growth factor (VEGF), an endothelial-specific mitogen that increases vascular permeability and has also been shown to be present in human atherosclerotic lesions, as compared with the physiological levels of shear stress. These changes in VEGF expression may suggest a possible molecular mechanism for increased endothelial permeability in regions of disturbed flow with low shear stress 66. All of these changes induced by disturbed flow as compared with laminar flow are of particular interest because of the focal nature of atherosclerosis along the vascular tree with a particular propensity for regions exposed to disturbed flow.

The induction of genes in ECs exposed to shear stress is believed to involve the activation of a variety of transcription factors, including nuclear factor-κB (NF-κB), early growth factor-1 (Egr-1), and activator protein-1 (AP-1), which contains c-fos and c-Jun. Using a step flow chamber that simulates some features of flow pattern occurring at branch points, Nagel et al. 67 demonstrated that ECs subjected to disturbed flow with spatial variations of shear stress exhibit increased levels of localized NF-κB, Egr-1, c-Jun, and c-fos in their nuclei, as compared with the cells exposed to unidirectional laminar flow or maintained under static conditions. Using the same model, Chiu et al. 68 examined the long-term effects of disturbed flow on the expression of ICAM-1, VCAM-1, and E-selectin on ECs by immunofluorescence staining using antibodies against these proteins. The exposure of ECs to disturbed flow for 24 h leads to positive fluorescence staining for ICAM-1 and E-selectin expressions, but not for VCAM-1. Sterol regulatory element binding proteins (SREBPs) are activated in response to sterol depletion to result in increases in the expressions of LDL receptor, cholesterol synthase, and fatty acid synthase. In contrast to the transient activation of SREBPs by laminar flow, disturbed flow applied to ECs in a step flow channel causes a sustained activation of SREBP-mediated gene expression and hence enhanced LDL uptake and lipid synthesis 69. Such differential regulations of transcription factor and gene and protein expressions by disturbed versus laminar flows indicate that regional differences in blood flow patterns in vivo, particularly the presence of spatial shear stress gradients, may represent important local modulators for EC signaling and gene expression at anatomic sites predisposed for atherosclerotic development.

Effects of temporal gradient in shear stress on EC signaling and gene expression

In addition to the spatial gradient of shear stress at vessel bifurcations and in the step flow channel, the temporal gradient of flow application also regulates EC functions. It has been demonstrated that the ERK phosphorylation and the expressions of c-fos, PDGF-A, and MCP-1 induced by increase in flow as a step (abrupt onset to reach a plateau) or an impulsive (abrupt application for 3 s only) function 70, 71 do not occur with a ramped increase in flow (shear stress gradually increased at flow onset). The differential modulations of MCP-1 and PDGF-A expressions by these different types of shear flows have been attributable to the corresponding changes in their respective transcription factors NF-κB and Egr-1, and these changes are mediated by NO 70. Furthermore, White et al. 72 have shown that ramp flow application can eliminate the enhanced EC proliferation at the reattachment area in the step flow channel seen with a step increase in flow. The cell proliferation induced by high temporal gradient in shear involves the activation of ERK in ECs 73. The increase in EC membrane fluidity and the consequent ERK and JNK activation induced by the application of laminar shear as a step function also do not occur with ramp flow 33. Using the isolated vessel ex-vivo perfusion system, Butler et al. 74 have shown that the initial potent and transient vasodilation induced by flow is dependent on the ramping rate of the shear flow and that the second phase of modest and sustained vasodilation is dependent on the shear magnitude. All these findings indicate that temporal gradient in shear stress plays important roles in modulating signaling and gene expression in ECs and consequently their functions.

Genomic analysis of gene expression profiles in ECs in response to shear stress

Several in-vitro studies using genomic approaches have identified a number of pathophysiologically relevant genes in ECs that are regulated by different types of shear stresses, including high and low laminar shears and disturbed flow 75–79. The results from these studies have suggested that high-shear laminar flow modulates EC gene expressions and functions that are protective against atherogenesis, whereas disturbed flow upregulates proatherosclerotic genes or proteins that promote development of atherosclerosis. To assess the modulation of gene expression profiles in ECs induced by mechanical forces that are actually present in the atherosclerosis-susceptible and atherosclerosis-resistant regions of human arteries, Dai et al. 80 have analyzed the flow patterns present in the human carotid bifurcation, using three-dimensional computational fluid dynamic analyses based on the actual geometries and flow profiles measured by magnetic resonance imaging and ultrasound. Their results showed that athero-prone and athero-protective waveforms of shear stress differentially regulate EC gene expression. The athero-prone waveform caused upregulation of a number of genes encoding proinflammatory functions (e.g. IL-8, pentaxin-related gene (PTX3), chemokine receptor 4 (CXCR4), and tumor necrosis factor receptor superfamily, member 21 (TNFRSF21)) and angiogenesis (e.g. placental growth factor (PGF), connective tissue growth factor (CTGF), and cysteine-rich 61 (CYR61)), and genes implicated in atherogenesis (e.g. thrombospondin 1 (THBS1), matrix metalloproteinase 1 (MMP1), and pleckstrin homology-like domain family A member 1 (PHLDA1 or TDAG51)). In contrast, the athero-protective waveform of shear stress increased the expression of sets of genes that prevent development of atherosclerosis (such as C-type natriuretic peptide (CNP), KLF-2, and those related to the NO pathway, including eNOS, guanylate cyclase 1 α3 (GUCY1A3), and argininosuccinate synthetase). This approach using actual profiles present in the atherosclerosis-susceptible and -resistant regions of human arteries facilitates the identification of genes that may have direct pathophysiological relevance to the atherosclerotic disease process in vivo.

Effects of different flow patterns and shear stresses on EC interaction with blood components

Atherosclerosis is a multifactorial disease involving a complex array of circulating blood cells (e.g. monocytes, lymphocytes, and platelets) and plasma components (e.g. lipoproteins), their interactions with vascular cells of the arterial wall, and the effects of flow pattern on mass transfer. Adhesion of circulating white blood cells (WBCs), most notably the monocytes, to and subsequent transmigration across the EC monolayer are early events in atherogenesis 81. The effects of different flow patterns and shear stresses on interactions between blood cells and biological or synthetic surfaces have been studied in vitro 68, 82–86. Investigating the adhesion of human platelets to collagen-coated surfaces in, and downstream of, a recirculation eddy distal to a tubular sudden expansion, Karino and Goldsmith 82 demonstrated a peak platelet adhesion within the recirculation eddy, while the adhesion was minimal at the reattachment flow area. In addition, the presence of erythrocytes was found to cause a marked increase in adhesion of platelets in the recirculation eddy. Pritchard et al. 83 found an increase in adhesion of monocytes on a chemotactic peptide-coated silicone surface in the disturbed flow region downstream of the tubular sudden expansion site. Barber et al. 84 reported that the arrest of monocytes on ECs occurs preferentially in the vicinity of the reattachment point in recirculation flow. Hinds et al. 85 found that flow patterns and biological activities of the surface are the major factors responsible for WBC adhesion, with pulsatile flow causing a lesser cell adhesion to E-selectin-coated surface than steady flow. Skilbeck et al. 86 investigated the adhesive behavior of neutrophils to P-selectin-coated surface under disturbed flow by microscopic observation and computational simulation. By using a step flow channel, Chiu et al. 68 demonstrated that the monocytic THP-1 cells exhibit prominent adhesion to tumor necrosis factor (TNF)-α-stimulated ECs in the region near the step and the reattachment point, but they show virtually no adhesion to unstimulated ECs. This regional difference in the distribution of monocyte-EC adhesion under disturbed flow may be attributable to 1) the altered expression of adhesive proteins such as ICAM-1 and E-selectin on EC surfaces, and 2) the enhanced collisions and prolonged contacts between the circulating monocytes and ECs, as a result of a higher near-wall concentration, a longer residence time, a higher normal velocity component towards the wall, and a smaller tangential velocity component along the wall in the disturbed flow region 68. Using the same model, Chen et al. 87 further demonstrated that disturbed flow can significantly increase the adhesion and transmigration of neutrophils, peripheral blood lymphocytes, and monocytes, particularly in the reattachment area. All these findings demonstrate the importance of complex flow patterns with altered shear stress in modulating interactions between the WBCs in the flowing blood and ECs, and this may contribute to the regional propensity for WBC recruitment in areas of prevalence of atherosclerotic lesions.

Summary and conclusions

Atherosclerosis, while clearly associated with several systemic risk factors (e.g. hyperlipidemia, hypertension, smoking, obesity, and diabetes), has a preferential localization pattern at the outer edges of blood vessel bifurcations and at points of blood flow recirculation and stasis. In these predisposed locations, fluid shear stress on the vessel wall is significantly lower in magnitude and exhibits directional changes and flow separation with high gradients; these features are absent in the straight part of the vascular tree which are generally spared from atherosclerosis. This striking correlation between regional hemodynamics and atherosclerosis has motivated many studies that have attempted to define a mechanistic role for hemodynamic factors, especially different flow patterns and the associated variations of shear stress, in the pathogenesis of atherosclerosis.

Vascular ECs are directly exposed to local changes in shear stress, and their dysfunction has been well recognized as a critical early event in atherosclerosis. In this review, we have summarized the current findings on the effects of different flow patterns and the associated shear stress variations on ECs, in terms of their signal transduction, gene expression, structure, and functions (for summary see Table I), which have been implicated in the initiation and progression of atherosclerotic lesions. In relatively straight segments of an artery with a laminar flow and a physiological level of shear stress, ECs are aligned and elongated in the direction of flow; this is in contrast to the more polygonal appearance without a clear orientation in areas of flow disturbance with altered shear stress. These morphological changes are accompanied by increases in cell turnover and DNA synthesis and a sustained activation of SREBP, which may respectively result in increases in permeability to macromolecules, such as lipoproteins, and a sustained increase in the SRE-mediated transcriptional activation of EC genes encoding for LDL receptor, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase, and fatty acid synthase, all of which promote lipid accumulation at the branch points.

Table I.  Summary of effects of different flow patterns and associated shear stresses on EC and vascular biology.

Laminar shear stress in a physiological range activates signaling pathways that induce endothelial elaboration of a number of factors that promote vasodilation (e.g. increased expression of eNOS and production of NO) and inhibit adherence of circulating blood elements (e.g. reduced expression of adhesion molecules and chemotactic proteins such as VCAM-1 and MCP-1). Several atheroprotective genes, e.g. antioxidant, anti-inflammatory, anticoagulant, and antiapoptotic genes, are upregulated by sustained laminar shear stress with a clear direction. In contrast, disturbed flow with a low and oscillating shear stress and a high shear stress gradient elicits factors that impair endothelium-mediated vasodilation (e.g. reduced expression of eNOS and production of NO) and increase adhesion of circulating blood elements (e.g. increased expressions of ICAM-1, E-selectin, MCP-1, and NF-κB). Transcriptional profiling of ECs in different flow regimes reveals that ECs exposed to disturbed flow with a low and reciprocating shear stress have significantly higher levels of a number of pathophysiologically relevant genes whose products may serve proinflammatory, procoagulant, proliferative, and proapoptotic functions, and hence promote atherosclerosis. All these findings indicate that laminar shear stress in a physiological range maintains vascular homeostasis and plays protective roles against atherosclerosis; whereas alterations of EC biology by disturbed flow with low and reciprocating shear stress would predispose these arterial regions to atherogenesis.

Atherogenesis involves interactions of multiple factors, including a complex array of circulating blood cells and plasma components, their interactions with the cells and matrix proteins of the arterial wall, and the effects of flow patterns on mass transfer. Investigations on EC responses to different flow patterns and shear stresses will provide important information concerning alterations in vascular signaling, gene expression, and function in the disease-prone regions. A major challenge in this field is the integration of a large body of data on EC responses to flow pattern and shear stress at the signaling and gene expression levels to identify useful biomarkers for atherosclerosis and to discover novel molecular targets, thus facilitating the development of new therapeutic strategies for this pathological process that underlies many cardiovascular diseases.

Acknowledgements

This work was supported by National Heart, Lung, and Blood Institute Grants HL080518 and HL085159 (to SC); National Health Research Institutes (Taiwan) Grant ME-097-PP-06 (to J-JC); and National Science Council (Taiwan) Grants 97-3112-B-400-009 and 97-2628-B-400-002-MY3 (to J-JC).

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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