Animal, In Vitro, and Ex Vivo Models of Flow-Dependent Atherosclerosis: Role of Oxidative Stress

Amir Rezvan; Chih-Wen Ni; Noah Alberts-Grill; Hanjoong Jo

doi:10.1089/ars.2010.3365

. 2011 Sep 1;15(5):1433–1448. doi: 10.1089/ars.2010.3365

Animal, In Vitro, and Ex Vivo Models of Flow-Dependent Atherosclerosis: Role of Oxidative Stress

Amir Rezvan ¹, Chih-Wen Ni ², Noah Alberts-Grill ¹, Hanjoong Jo ^1,,^2,,^3,^✉

PMCID: PMC3144429 PMID: 20712399

Abstract

Atherosclerosis is an inflammatory disease preferentially occurring in curved or branched arterial regions, whereas straight parts of the arteries are protected, suggesting a close relationship between flow and atherosclerosis. However, evidence directly linking disturbed flow to atherogenesis is just emerging, thanks to the recent development of suitable animal models. In this article, we review the status of various animal, in vitro, and ex vivo models that have been used to study flow-dependent vascular biology and atherosclerosis. For animal models, naturally flow-disturbed regions such as branched or curved arterial regions as well as surgically created models, including arterio-venous fistulas, vascular grafts, perivascular cuffs, and complete, incomplete, or partial ligation of arteries, are used. Although in vivo models provide the environment needed to mimic the complex pathophysiological processes, in vitro models provide simple conditions that allow the study of isolated factors. Typical in vitro models use cultured endothelial cells exposed to various flow conditions, using devices such as cone-and-plate and parallel-plate chambers. Ex vivo models using isolated vessels have been used to bridge the gap between complex in vivo models and simple in vitro systems. Here, we review these flow models in the context of the role of oxidative stress in flow-dependent inflammation, a critical proatherogenic step, and atherosclerosis. Antioxid. Redox Signal. 15, 1433–1448.

Introduction

The relationship between atherogenesis and blood flow or arterial wall shear stress has been studied for over 40 years (16, 17, 28, 33, 37, 47, 55, 64, 107, 170). Although some suspected that mechanical damage to the endothelium caused by suction forces (164) or high shear stress (47) was grounds for atherosclerosis, prevailing evidence supports that atherosclerosis is correlated to areas of flow separation (43, 64, 189), low shear stress (17, 18, 189), and oscillatory flow (89). The role of high shear stress re-emerged later in the context of plaque vulnerability (99). Apart from the magnitude and direction of shear stress, spatial (119) and temporal (4, 122, 180) gradients of shear stress are also important determinants of endothelial cell (EC) response. Moreover, a recent study from our group has shown direct evidence demonstrating that disturbed flow indeed leads to rapid development of atherosclerosis in a mouse model (121). In addition, this disturbed flow-induced atherosclerosis was mediated in part in an NADPH oxidase (Nox)-dependent manner (121). Here, we review these in vivo, ex vivo, and in vitro models in the context of studies designed to understand the role of oxidative stress in flow-mediated inflammation, a critical proatherogenic step, and atherosclerosis.

Animal Models of Atherosclerosis

Animal models play an essential role in helping us understand the pathophysiology of disease. Although no animal model is a perfect replica of the biological and pathophysiologic process in patients, they provide us with conditions that can be manipulated to clarify the process in such ways that would be impossible or unethical to perform in humans. Many of the animal models that will be discussed have been used effectively to demonstrate the important role of oxidative stress and nitric oxide (NO) signaling in atherosclerosis.

Many different animal species have been used as models for atherosclerosis (2, 69, 75). Different strains of the same species have varying susceptibility to atherosclerosis (75, 124). Some animals such as pigeons have naturally occurring lesions, whereas in others such as mice, an intervention such as genetic manipulation, special diet, or surgical intervention is needed to produce plaque. In many cases, interventions are used to accelerate plaque formation or alter the severity/complexity of the lesions.

Larger animal models such as pigs, minipigs, and primates benefit from larger arterial size, and are therefore more relevant to human studies in addition to providing larger sample sizes of protein and RNA as well as opportunities for percutaneous interventions. The mouse has become one of the most important animal models (182) because of its numerous attributes such as relatively low cost, amenability to genetic modifications (knockout [KO] or transgenic mice), a completely mapped genome, availability of reagents (antibodies, siRNAs, microRNAs, etc.), and manifestation of cardiovascular diseases resembling at least some aspects of human pathophysiology.

Hypercholesterolemia-induced atherosclerosis

Although early attempts to cause atheromas in mice were unsuccessful, certain strains of mice do form atheromas in certain experimental models (124, 168). Many mouse models of atherosclerosis rely on inducing hypercholesterolemia by a combination of genetic mutation and high-fat diet. The most susceptible inbred mouse strain commonly used is the C57BL/6J strain. The susceptibility to atherosclerosis in different mouse strains does not correlate with the degree of hypercholesterolemia induced (124). In the past two decades, multiple genetic modifications have helped produce hyperlipidemic mice. Two of the most widely used genetic manipulations are disruption of the apolipoprotein E (ApoE) gene (127, 130, 193) and deficiency of the low-density lipoprotein receptor (70).

Many different custom diets are used in animal models to induce or accelerate atherosclerosis. There are two commonly used types of atherogenic diet in hyperlipidemic mouse models. Paigen's high-fat diet includes cholate and was originally made by mixing the Hartroft–Thomas diet (167) with a nonatherogenic diet (123). The Western diet contains no cholate and is considered less inflammatory and less potent in its atherogenic properties, but is also shown to be capable of promoting atherosclerosis in genetically deficient mice (100, 130).

Arterial injuries inducing atherosclerosis

Different models of arterial injury have been used, mostly as models of vascular remodeling and wound healing. Although in many of these models local shear stress is affected because of remodeling of the vessel in response to the injury, these are not regarded as models for flow-induced atherosclerosis.

An immunologic vascular injury by repeated injection of foreign proteins produced cellular lesions in larger arteries of rabbits fed an atherogenic diet (59, 110). A drying model of endothelial injury in rats (30) was used as the main arterial injury model in rodents until a wire injury model was established in the mouse (101) and followed later by balloon injury models (42, 115). The wire and balloon injury models are appropriate models to study restenosis in the context of vascular injury because of percutaneous interventions. Electrical injury stenosis (15) and chemical injury stenosis (82, 194) both induced from the adventitial side of blood vessels cause a transient thrombus formation and eventually lead to neointima formation.

The nonconstrictive perivascular cuff model initially used in rabbits (10) is another example of vascular injury induced from the adventitia leading to neointimal thickening, though in a more inflammation-based model. The role of possible local ischemia because of vasa vasorum occlusion was suggested in this model. The advantage of this model is that the vascular cells are not directly killed by an electric current or chemical. This model was the basis of constrictive perivascular cuff models that will be discussed below and was later modified for use in mice, resulting in accelerated atherosclerosis in a hyperlipidemic mouse model (61, 91, 145) and hyperlipidemic rabbits (183).

Animal models of flow-dependent atherosclerosis

Since atherosclerosis is a local disease, occurring mostly in areas of low and oscillatory shear (OS) stress—key features of disturbed flow—many have focused on studying the areas of naturally occurring disturbed flow in animal models, whereas others have attempted to create areas of disturbed flow to mimic the shear stress profile experienced in areas of naturally occurring atherosclerosis. Shear stress levels vary not only in different regions of the arterial tree within each species, but also considerably between different species, with higher shear stress values generally seen in smaller animals (22). Change in vessel diameter in response to shear stress alterations is not only species dependent but also strain dependent (68).

Areas of naturally occurring disturbed flow

For many years, atherosclerosis research in animal models was performed mostly by studying spontaneous atherosclerosis in animals susceptible to atheroma formation (75). In all the animal models discussed above, in which no surgical intervention is performed, atherosclerosis is predominantly seen in areas of disturbed flow. A disturbed pattern of flow can be found in many different areas of the arterial tree, including, but not limited to, the aortic root, lesser curvature of the aortic arch, root of the innominate artery, carotid bifurcation, branching of the celiac artery from the abdominal aorta as well as certain regions in the coronary system (3, 13, 26, 35, 41, 84, 93, 106, 161, 162). The predilection of these sites to atherogenesis is what brought the relationship of mechanical forces and atherosclerosis to the attention of investigators. Although these areas can be used to study the effects of disturbed flow on endothelial biology, including gene and protein expression, in many animals especially in mice, a hyperlipidemic model needs to be added to induce atherosclerosis in these regions.

The major advantage of using these areas of naturally occurring disturbed flow is the pathophysiologic relevance, as these are the areas that atheromas form in atheroprone species such as humans. These areas are chronically exposed to disturbed flow patterns. Therefore, although they are appropriate models for long-term atheroma formation, they are inadequate for assessing the effects of acute changes in shear stress. They may have adopted compensatory mechanisms to the disturbed flow pattern and other local conditions may also contribute to the disease. Another drawback is that in most of these models, the area exposed to disturbed flow is usually a very confined area. As such, the sample size for collecting protein and mRNA for analysis is very limited (181). Still, examining areas of naturally occurring disturbed flow is the oldest model used to look at the effects of shear stress on atherosclerosis and as such has produced the largest body of information currently available in the field (29, 34, 76, 125). For example, these areas of naturally occurring disturbed flow were used to show that gp96^phox deficiency in phagocytes did not affect atherosclerosis formation (83) and that p47^phox is required for atherosclerotic lesion progression in ApoE KO mice (6). The ApoE KO on high-fat diet model was recently used to show the role of Nox2-mediated reactive oxygen species (ROS) production on atherosclerosis (78) as well as the protective role of dietary polyphenols on atherosclerosis (103).

Models inducing acute changes in shear stress

Although some interventions that likely changed flow patterns and shear stress were found to produce severe atherosclerosis—such as the coarctation of proximal aorta producing severe atherosclerosis in experimental dogs (143)—the specific role of acute changes in shear stress was not assessed until the 1980s. The initial models were used to show the effect of shear stress on vascular diameter by creating an arterio-venous (A/V) shunt (79, 190), placing a restrictive clip around the artery (56), or changing the viscosity of blood (109) as well as showing the effect of shear stress on EC morphology in vivo (95). Importantly, this model was used to demonstrate that the change in vascular diameter in response to shear stress is dependent on intact vascular endothelium (90).

With technological advances and development of faster computers and more powerful software, the accuracy in calculation of shear stress in the arterial tree has increased significantly in the past few decades. More recently, finite element modeling and computational fluid dynamic methods have allowed investigators to assess wall shear stress more accurately in complicated and realistic situations of pulsatile flow conditions and curving and branching vessels (20, 65, 66, 121, 133, 136, 160, 161, 188).

A/V fistula

One of the first models to incorporate an intervention causing acute change in shear stress is the A/V fistula (190). In this model blood flow is increased in the artery from which the fistula is created. It was shown that in response to the increased shear stress, the lumen of the artery dilates to the extent that the final shear stress is not significantly different from the original shear stress. In humans, the effect of increased shear stress on vascular remodeling caused by A/V fistula has been shown in chronic kidney disease patients who undergo A/V fistula formation for the purpose of dialysis access (50). This model was used to show the regulatory role of p47^phox component of Nox on shear stress-induced vascular remodeling (19).

Vascular grafts

The use of vein grafts as a model for atherosclerosis was originally developed to study the pathophysiology of atherosclerosis in coronary artery bypass graft patients. The saphenous vein graft is widely used for the purpose of coronary artery bypass. However, it is now well known that the occlusion rate in these venous grafts is much higher than when using an arterial graft such as the internal mammary artery. To better understand the pathogenesis of venous graft occlusions, animal models of venous grafts have been used (38, 40, 58, 63, 98, 150, 195). This method involves end-to-end transplantation of the inferior vena cava or external jugular veins to the common carotid artery (Fig. 1). Although the fluid dynamics involved in this model have not been extensively studied, one can speculate that because of the larger diameter of the engrafted vein compared to that of the common carotid, lower shear stress is achieved in the engrafted vein compared with the contralateral artery, which is usually used as a control. Although this lower shear stress may be a contributing factor to atherogenesis in this model, owing to significant inherent differences between venous and arterial vessels, the relative contribution of change in shear stress will be very difficult to determine. This model has been modified as a chimeric model using human coronary artery grafts in mice (178). It also has the potential to allow the investigator to use a graft from a specific KO animal and create a model in which the investigator can effectively study the local KO effect of a certain gene in the process of atherosclerosis or vascular remodeling.

FIG. 1. — **Schematic representation of vein bypass graft in the common carotid artery.** The right common carotid artery (RCA) was ligated with an 8-0 silk suture **(A)** and dissected between the middle ties and passed through the cuffs **(B)**. The suture at the end of the artery was removed, and a segment of the artery was turned inside out to cover the cuff body **(C)**, which was fixed to the cuff with an 8-0 silk suture **(D)**. The right external jugular or vena cava vein segment was harvested and grafted between the two ends of the carotid artery by sleeving the ends of the vein over the artery cuff and suturing them **(E)**. *Arrow* indicates direction of blood flow. The cuff handle was cut off, and the vascular clamps were removed. Reprinted with permission from Zou *et al*. (195).

Constrictive perivascular cuff

The perivascular cuff model was modified to a constrictive cuff used in hyperlipidemic animals to induce rapid atherosclerosis (23–25, 131, 132, 176, 177). In this model, while the vessel region constricted by the cuff is exposed to higher shear stress, a proximal section of the post-constriction area is exposed to disturbed flow giving rise to low and OS stress patterns. An example of a recent such device that also incorporates a tapered lumen providing different levels of shear stress within the cuff is shown in Figure 2. This model has the ability to produce distinct flow patterns in neighboring regions. A drawback of this model is the requirement for direct manipulation of the vessel adventitia that may resemble the injury effect seen in the nonconstrictive perivascular cuff model. This model has been used to show the role of shear stress on endothelial NO synthase (eNOS) localization (25).

FIG. 2. — **Perivascular cuff model and its shear stress patterns. (A)** The cast consists of two longitudinal halves of a cylinder with a conical lumen. **(B)** The theoretical design with induction of large vortices downstream of the cast in the carotid artery. Additionally, the conical lumen induces a stenosis of the vessel, causing a gradual increase in vascular shear stress in the cast area. A region of low shear stress is created upstream of the cast. Reprinted with permission from Cheng *et al*. (25).

Ligations: complete, incomplete, and partial

Incomplete ligation

The incomplete ligation of an artery to assess the effect of shear stress on atherosclerosis was first used in Yucatan micropigs (148). By causing a 50% aortic stenosis, the authors showed that increased shear stress had a protective role against plaque formation in a hyperlipidemic model. More recently, a modified version of this model with 80% stenosis was used to show features of vulnerable plaque (71, 153).

Complete ligation

Complete ligation of the carotid artery has been widely used in rodents and causes vascular remodeling, neointimal hyperplasia (39, 53, 88, 108, 112, 115, 126, 134, 138, 156, 184, 191), and used to demonstrate the role of NO and ROS in this remodeling (80, 88, 102, 105, 115, 117, 139, 146, 185, 187) as well as atheroma formation when used in hyperlipidemic animal models (31, 72, 77, 81, 94, 102, 120, 139, 145, 174, 183, 192). The complete ligation model leads to abrupt cessation of blood flow, essentially reducing wall shear stress to zero and therefore can be accounted as a shear stress modifying model. However, because of thrombus formation and significant endothelial injury as well as the low relevance of no-flow conditions to atheroma formation in humans, it may not be a suitable model to study the effects of shear stress in atherosclerosis and is better viewed as a model of arterial injury.

Partial ligation model

The complete ligation model has evolved into a modified partial ligation model of the carotid artery (85, 86, 111, 141, 142, 159, 163) that was shown to cause reduced flow in the ligated artery and shear stress-dependent vascular remodeling of the carotid artery in mice in an NO/ROS-dependent manner. We recently characterized this model further and showed that by ligating the internal carotid, the occipital, and the external carotid after the branching of the superior thyroid artery, allowing common carotid blood flow only through the superior thyroid artery (Fig. 3), not only is the flow rate significantly reduced, but also a flow reversal pattern is seen during diastole, giving rise to a combined low and OS stress pattern that is characteristic of areas of disturbed flow in the arterial tree (121).

FIG. 3. — **Schematic of partial ligation of the left common carotid artery (LCA) branches.** Three branches of the LCA (external carotid artery [ECA], internal carotid artery [ICA], and occipital artery [OA]) were ligated using 6-0 suture, while leaving the superior thyroid artery (STA) patent to create oscillatory and low shear stress in the LCA. Reprinted with permission from Nam *et al*. (121). LSA, left subclavian artery; RSA, right subclavian artery.

With this model and a high-fat diet feeding, we have directly demonstrated that acutely imposed disturbed flow induces robust atherosclerosis by 2 weeks and complex lesion formation by 4 weeks after partial ligation in the common carotid of ApoE KO mice (121). We have also shown that disturbed flow alters EC gene expression and p47^phox-dependent ROS formation within 2 days and endothelial dysfunction within 7 days (121). Moreover, we used this model to test the role of ROS in flow-induced atherosclerosis by comparing ApoE-null mice and p47^phox_ApoE double KO mice. We found that disturbed flow increased superoxide production in ApoE KO mice that was significantly blunted in p47^phox_ApoE double KO mice. We also found that flow-induced atherosclerosis in p47^phox_ApoE double KO was significantly less in the early phase (2 weeks postsurgery) than ApoE KO, but this difference began to disappear by 3 weeks postsurgery (121). These results suggest that p47^phox-dependent ROS plays a critical role in early atheroma formation, but ROS produced from other sources become more important in the late phase of the disease. The alternative sources of ROS are not known yet, but mitochondria and uncoupled eNOS are some of the potential candidates. Using this model, we have also shown that low and OS is associated with impaired GTP cyclohydrolase-1 phosphorylation and reduced tetrahydrobiopterin levels in vivo (97). In this model, the left common carotid artery, where atheroma develops, is un-touched or not manipulated during the partial ligation surgery to minimize direct injury to the common carotid. In fact, performing sham partial ligations, including performing the surgery and tying loose knots around the branches of the common carotid artery, does not result in atheroma formation within the timeframe studied. An additional advantage of this model is the availability of the large portion of the carotid arteries that allows easy and reproducible intimal RNA isolation, enabling RNA studies such as qPCR and genome-wide analysis of cDNA and microRNA to identify mechanosensitive transcripts and pathways.

In Vitro Models for Shear Stress Studies

To investigate how local hemodynamic conditions regulate EC function in vivo, several in vitro systems have been developed (140). Devices such as the parallel-plate flow chamber, vertical step flow chamber, cone-and-plate viscometer, modified cone-and-plate shear apparatus, and microfluidics devices have allowed for controlled experiments on cultured ECs (27, 32, 60, 140, 158). The cone-and-plate and parallel-plate flow chamber are two of the most popular in vitro shear devices. Here, we will discuss prototypes of each model.

Cone and plate

The first well-characterized in vitro shear stress device was introduced by three pioneers of endothelial mechanobiology—Forbes Dewey, Peter Davies, and Michael Gimbrone—using the geometry of a cone-and-plate viscometer (14, 36). In this system, shear stress is produced by rotating a cone over a stationary plate containing ECs cultured on cover slips. Using this device, it was demonstrated for the first time that shear stress can regulate EC shape and orientation as well as more complex biological functions such as wound regeneration, fluid endocytosis, and platelet/endothelium interactions. Although this original cone-and-plate or viscometer system has since been modified by numerous groups, including us, it ushered a new field of endothelial mechanobiology.

A modified cone-and-plate design was published in 1984 by Franke et al. (46, 151). The authors fitted a transparent polycarbonate cone into a Plexiglas holder and connected the cone to a speed-controlled motor with variable rotational velocities. The entire cone-and-plate system was connected to an optical system, which allowed direct observation in a real-time manner in response to shear stress. In this study, the results clearly showed that endothelial stress fibers can be induced by a 3-h exposure of ECs to fluid shear stress of 2 dyn/cm², suggesting that shear stress may act directly on the stress fiber system without affecting cellular shape and orientation.

The disadvantages of the cone-and-plate devices have been addressed recently (8, 9, 155). Blackman et al. developed a new controlled cell shearing device (Fig. 4) based on the cone-and-plate viscometer that utilized a microstepper motor technology to independently control the dynamic and steady components of the hydrodynamic shear–stress environment (8). This system also integrated a fluorescence microscopy system to allow real-time monitoring of cellular responses. These devices have been used to reproduce atherogenic or atheroprotective flow wave forms acquired in vivo, allowing the observation of endothelial responses to disease-relevant shear conditions (1, 32). Although this is a state-of-the-art device, a major disadvantage is the relatively high cost of custom manufacturing the system and culture dishes.

FIG. 4. — **Schematic of the controlled cell shearing device.** The schematic shows the dynamic two degrees-of-freedom cone assembly, z-axis translation *via* dual micrometers, and rotation *via* microstepper motor. Reprinted with permission from Blackman *et al*. (8).

Tarbell and colleagues modified the cone-and-plate system to measure water flux across endothelial monolayer under shear stress (154). On the basis of a cone-and-plate apparatus, the luminal compartment contained a cylindrical disk, which was rotated by a drive motor assembly to produce a defined shear stress on the endothelial monolayer. With this special design they demonstrated that shear stress increases hydraulic conductivity of cultured endothelial monolayer through a cellular mechanism involving signal transduction.

Our lab has also developed a modified cone-and-plate shear apparatus (51, 74) (Fig. 5). The entire shear system except for the personal computer controller unit was housed in a humidified tissue culture incubator (5% CO₂, 37°C). The cone was rotated either back and forth or unidirectionally through an in-house computer program and a stepping motor to generate oscillatory and laminar shear (LS) patterns, respectively, or to mimic in vivo flow profiles. The shear system was designed to be used with a 10 cm tissue culture dish (Falcon) and the Teflon lid was designed to allow free gas exchange between the cells and the incubator environment, while preventing contamination. We have used this system to identify several shear sensitive genes and their biological function. For example, we have shown that OS stress induces expression of bone morphogenetic protein 4 (BMP4), angiopoietin 2, peroxiredoxin, and cathepsins L and K, and investigated their roles in inflammation, vasculogenesis, vascular remodeling, and oxidative stress (21, 116, 128, 129, 157, 158, 171). The advantages of this modified system are that it is extremely simple to use (just put a cone to a standard 10 cm culture dish), and is well suited for chronic studies (hours to days) with virtually no threat of contamination because the cone is housed in a lid unit that sits on the dish. The system also provides large quantities of protein and RNA from single 10 cm dishes. However, there are some disadvantages to using this type of device. For example, EC monolayers are not subjected to uniform shear stress levels as a shear–stress gradient is produced from the center toward the edge of the dish. In addition, our system has a smaller cell-to-volume ratio and does not permit continuous sampling of the cell culture medium. It also permits the culture medium to evaporate, which requires replenishing with fresh medium and is not set up to allow us to monitor cell behavior in real time.

Using our cone-and-plate shear device, we have shown that exposure of ECs to OS stimulates ROS production from Noxs, which in turn results in monocyte adhesion (157). Hwang et al. have shown that OS increases Nox2 and Nox4 mRNA level after 4 and 8 h of exposure (67, 157). Similarly, our group has shown that Nox1 and Nox2 were increased after 24-h exposure to OS stress (67). These findings prompted the question of whether BMP4 produced in ECs by OS is directly responsible for production of ROS from Noxs, which then leads to inter-cellular adhesion molecule 1 (ICAM-1) induction and monocyte binding. Our initial studies using pharmacological approaches via ROS scavengers such as N-acetyl-cysteine, the cell-permeable polyethylene glycol-catalase, polyethylene glycol-superoxide dismutase, and Tiron completely blocked OS- and BMP4-induced monocyte binding and ICAM-1 expression, demonstrating a role for ROS in these processes (67, 157). Further, we showed that mouse aortic ECs obtained from Nox KO mice lacking p47^phox (MAE-p47^−/− cells) (67) did not produce ROS in response to OS or BMP4. ROS production in these cells was rescued by transfecting them with p47^phox cDNA. A similar approach was used in MAE-p47^−/− cells to demonstrate that OS and BMP4 stimulate monocyte adhesion by a mechanism dependent on ROS derived from p47^phox-based Noxs (157). These findings suggest that exposure of ECs to OS induces BMP4 production, which in turn triggers proinflammatory and proatherogenic responses of ECs by increasing ROS production from Noxs.

Parallel-plate flow chamber

Frangos, McIntire, and colleagues (44, 45) developed a parallel-plate flow chamber, which has been widely used and modified by many groups (87, 92, 96). The design of the flow chamber consists of a machine-milled polycarbonate plate, a rectangular Silastic gasket, and a glass slide (or cover slip) with the attached EC monolayer (Fig. 6). These were held together by a vacuum maintained at the periphery of the slide, forming a channel of parallel-plate geometry. Flow was driven either by the hydrostatic pressure head between the two reservoirs to produce steady flow or via cam-driven clamps upstream of the chamber to produce pulsatile flow.

FIG. 6. — **Parallel-plate flow chamber and schematic diagram of flow loop. (A)** Parallel-plate flow chamber. The polycarbonate plate, the gasket, and the glass slide with the attached cells are held together by a vacuum, forming a channel of parallel-plate geometry. Medium enters at entry port, through slit, into the channel, and exits through slit, and exit port. Reprinted with permission from Lawrence *et al*. (92). **(B)** Drawing of flow loop. Reprinted with permission from Frangos *et al*. (44).

Parallel-plate flow chamber devices have been used to document changes in EC morphology (96) and metabolism (44, 45) in response to shear stress, as well as to successfully model leukocyte–endothelium adhesion interactions under flow conditions (92). Thereafter, several modified designs have been used to investigate many important topics. For example, to study the effects of shear on EC monolayer permeability, we attached the flow chamber to a circulating luminal perfusion loop and a noncirculating abluminal loop (73). Usami et al. published a modified parallel-plate system in 1993 that used a flow chamber with a center arrow-shaped channel capable of generating variable shear stresses within the same flow field without changing the flow rate or gap width because of the geometry of the channel (175). This design could generate a variable shear stress, because of the geometry of the channel, within the same flow field without changing the flow rate or the gap width, starting from a predetermined maximum value at the entrance and falling to zero at the exit. Studies conducted using this device demonstated that expression of adhesion molecules such as vascular cell adhesion molecule 1 (VCAM-1) and E-selectin was suppressed proportional to increased shear stress in cultured human aortic ECs (173). Also, this gradient flow chamber has been used to study the effects of different shear rates on platelet adhesion onto immobilized fibrinogen and von Willebrand factor matrices (147).

Flow characteristics such as flow separation, recirculation, and reattachment in areas such as arterial bifurcations may directly contribute to the initiation of focal atherogenesis. Spatial and temporal gradients in shear stress overlap in atherosclerosis prone regions, and a specially designed flow device was needed to separate these two factors to determine their effects on atherosclerotic plaque growth. The sudden expansion flow chamber (172) and the backward-facing step flow chamber (57) were developed to create the separated flow streams by which ECs experience large spatial shear stress gradients. In the sudden expansion model, fluid flows from a narrow channel over a step expansion into a wider channel. The asymmetric expansion of the flow path leads to flow separation. Close to the expansion step, there is a re-circulating eddy with a flow direction against the main flow. Farther downstream, the flow reattaches and eventually re-establishes a unidirectional parabolic flow profile. In addition, the temporal gradient in the step flow chamber can be effectively eliminated by changing the rate of flow onset. In experiments on ECs, disturbed flow stimulated cell proliferation only when flow onset was sudden, and the spatial patterns of proliferation rate match the exposure to temporal gradients (57). A different design of flow system by Hsiai et al. was used to study the effect of various upstroke slopes of pulsatile flow, also known as shear stress slew rates (62). The inlet and outlet of a parallel channel was connected to symmetrical contractions and diffusers ensuring uniform velocity and preventing flow separation across the channel. This flow system was able to precisely control the frequency, amplitude, and time-averaged shear stress of pulsatile flow and allowed the investigators to study the effect of slew rates independent from other factors. Using this system, it was observed that EC remodeling was faster in response to higher slew rates at a given time-averaged shear stress.

The parallel-plate flow chamber is widely used by numerous groups with various modifications; however, setting up a flow system may not be easy for scientists without engineering background. As such, several commercially designed flow systems based on the parallel-flow chamber are available (GlycoTech, Flexcell, etc.). Brown and Larson compared the original and commercially designed (GlycoTech) flow chambers and concluded that the chamber from GlycoTech dramatically reduced reagents use and cell requirements and could be useful in a variety of shear experiments (12)

Coculture shear stress system: a modified parallel-plate system

Since the vessel wall is composed of several types of cells, including ECs, smooth muscle cells (SMCs), and fibroblasts, heterogenous cell–cell interactions could govern numerous biological events in both healthy and diseased vasculature. Coculture models place ECs in proximity to SMCs to better simulate the in vivo environment. Nackman et al. first developed a parallel-plate flow chamber into which a coculture permeable membrane is inserted (Fig. 7). In this model, ECs were cultured on one side of the membrane and exposed to laminar flow, whereas SMCs were cultured on the other side of the membrane and not directly exposed to flow (118). Using this system, they exposed the EC side of the coculture to low shear stress and showed that the proliferation of the neighboring SMCs was attenuated (118). Rainger et al. and Chiu et al. also established similar parallel-plate coculture systems (27, 137). It was shown that coculture of ECs with SMCs markedly increased the adhesion of flowing leukocytes to ECs (137). Further, LS stress inhibited expression of adhesion molecules such as ICAM-1, VCAM-1, and E-selectin in ECs induced by coculture with SMCs (27), suggesting that SMCs may induce inflammatory responses in ECs and LS stress acts as a protective regulator of atherogenesis (152).

FIG. 7. — **Schematic diagram of coculture apparatus inserted into aperture of parallel-plate flow device.** Reprinted with permission from Nackman *et al*. (118).

Microfluidic devices

The cone-and-plate and parallel-plate flow chamber are the most wildly used systems in shear stress studies. However, these gold standard systems are not suitable for certain types of research such as high-throughput screening studies because of the large number of ECs needed and the large volumes of culture medium and reagents needed to maintain them. To address these issues, Schaff et al. have developed the vascular mimetic microfluidic chamber, which is designed to precisely control the input concentration of cells and reagents over time and to observe the leukocyte–EC interactions in real time (Fig. 8A) (149). Using this device, the authors examined the relationship between hydrodynamics and neutrophil recruitment. Another microfluidics system was designed to study the effects of shear stress on platelet adhesion (54). Gutierrez et al. demonstrated that the microfluidic devices made of polydimethylsiloxane (PDMS) sealed with a cover glass could be used to study dynamic platelet adhesion with volume requirements reduced to less than 100 μl per assay. In addition, the PDMS microfluidic device has also been further modified with a magnetic clamp to seal PDMS chips against cover glasses with cell cultures (169). It provides a reliable way for sealing microfluidic devices with little effect on the shear stress at the glass substrate during the perfusion. Moreover, microfluidic devices have been designed to study the responses of ECs exposed to pulsatile and OS stress in an integrated microfluidic chip with a pneumatic micropump (Fig. 8B) (152). These microfluidic devices show a great potential as a tool for an in vitro shear stress model with several benefits, including higher-throughput and reduced reagent use.

FIG. 8. — **Microfluidic devices used to study the effects of shear stress on endothelial cells. (A)** Schematic of the vascular mimetic device. The silicon master pattern produces a flow chamber consisting of four independently operated sets of channels, which are isolated by intervening vacuum lines. Reprinted with permission from Schaff *et al*. (149). **(B)** Schematic illustration of the microcirculatory system on the chip. A top view of the chip with tubings connected and a cut pipette tip inserted (filled with dye for observation). Reprinted with permission from Shao *et al*. (152).

Other in vitro systems

Samet and Lelkes developed a pulsatile flow chamber model of an artificial cardiac ventricle device and studied EC morphology as well as gene expression patterns in response to disturbed flow conditions (11, 144). Another in vitro shear device that merits mention is a chamber device in which ECs cultured on a filter membrane in a chamber can be exposed to shear stress, an oxygen concentration gradient, and low-density lipoprotein loading. Using this system, Warabi et al. have shown the dominant role of shear stress in gene expression patterns in an Nrf2-dependent manner (179).

Simultaneous shear and strain device

Although shear stress is well studied and considered to be an important factor in vascular biology, circumferential strain driven by the pulsing wall motion also showed significant effects on endothelial biology (7). The interaction of shear stress and strain may influence the responses of ECs, and a specific design of flow system has been designed to investigate EC biological responses to simultaneous OS stress and strain over a physiological range of stress phase angle (SPA) (114, 135). ECs were cultured on the inside walls of elastic, silicon rubber tubes, and a pulsatile flow loop was developed to generate OS stress and circumferential strain. The results of this study showed that strain tends to enhance the vasodilatory tendency, and this is modulated by the SPA (135), and it seems that the interaction of shear stress and strain can also influence vascular remodeling. Thus, this model could be used to further study multiple mechanical stimuli with different SPA and help to elucidate the detailed mechanisms.

Ex Vivo Organ Culture Models

In vitro models obviously provide a gold standard of experimental control, but fail to replicate the complex cell–cell and cell–matrix interactions that occur in vivo and likely play a central role in the relationship of oxidative stress, shear stress, and atherosclerosis. To account for this, ex vivo organ culture models have been to bridge the gap between in vitro and in vivo research on the relationship between shear stress and oxidative stress.

History and background

Ex vivo models of sufficient sophistication and physiological relevance to replicate in vivo conditions of pressure, shear, and stretch have existed since the early 1990s. In these models, explanted artery segments are canulated at either end in a culture medium bath and plugged into a perfusion circuit to allow perfusion of the arterial segment with directional fluid flow. Closed-circuit perfusion systems exist that provide control of intraluminal pressure and flow pulsatility and direction in a sterile environment with the potential for long-term organ culture studies (5, 48).

Ex vivo models of shear-induced oxidative stress

Ex vivo models have been used by researchers in the atherosclerosis field to elucidate vascular wall responses to a number of physiologic mechanical forces and other biological processes thought to be involved in atherogenesis (186). Some of these studies focused on the relationship between shear stress and oxidative stress. Gambillara et al. showed that plaque-prone hemodynamics such as low and especially OS stress reduced eNOS expression in explanted ex vivo cultured porcine carotid arteries (48). Disturbed flow also impaired endothelial function by making exposed endothelium nonresponsive to bradykinin treatment. eNOS is important in oxidative stress and atherosclerosis for producing NO, which functions as a vasodilator and atheroprotective factor. As shown by Lu and Kassab, NO levels in ex vivo cultured porcine arteries sharply drop after exposure to reverse flow because of shear-induced production of superoxide by ECs (104). This effect was inhibited by adding a cell-permeable free radical scavenger such as tempol. Further work has tied shear-dependent increases in superoxide production to the increased enzymatic activity of Nox under proatherogenic shear conditions (52). Ex vivo shear models have also been refined to study the effects of other important mechanical forces in the vascular environment in vivo in addition to shear stress (49, 113). To tease apart the effects of shear stress and circumferential cyclic stretch on oxidative stress and vascular wall remodeling, an ex vivo setup was used in which stretching force parallel to the vessel's length can be controlled in addition to flow dynamics. The authors show that although superoxide production and activity of wall-remodeling proteases are shear dependent, reduced cyclic stretch enhances these effects, especially within the vascular endothelium. Further, reduced stretch also abrogated SMC contractility (165, 166). The aforementioned studies demonstrate the promise of ex vivo organ culture techniques to dissect the complex interactions of mechanical stresses in the vascular environment in vivo such as shear and cyclic stretch, and piece together their contributions toward oxidative stress and atherosclerosis.

Perspectives

Here, we reviewed in vivo, in vitro, and ex vivo models that have been used to study the relationship of shear stress, endothelial biology, and vascular diseases such as atherosclerosis. As for in vitro models, two of the most widely used and best characterized are the cone-and-plate and parallel-plate shear devices. These systems and modified versions have been critical in understanding molecular insights by which shear stress regulates endothelial function and structure under simple conditions.

Ex vivo culture models of shear stress attempt to combine the best of both worlds from in vivo and in vitro systems. Although retaining the advantage of controlling experimental conditions such as shear stress, ex vivo studies can be carried out without the confounding drawback of having to work with cultured cells, which can often behave very differently from somatic cells in vivo. In addition, they can also maintain vascular cells in their native tissue environment, that, while sacrificing experimental simplicity, adds more biological realism to ex vivo models. These ex vivo models can be carried out under in vivo-like mechanical conditions, including pulsatile flow, cyclic stretch, and oscillatory or LS together in one package.

Although in vitro and ex vivo models have their respective merits in simplifying the model such that specific mechanisms can be studied with more clarity and ease, animal models are still required to test most hypotheses addressed by in vitro and ex vivo models. However, the complexity of animal models and the differences between species may make the conclusions derived from animal models difficult to interpret. It is therefore of paramount importance to realize the constraints of various animal models and to choose the most relevant model for a particular study. It is also critical to compare the results obtained from in vivo models that acutely induce flow changes to that of endogenous flow-disturbed (atheroprone) or stable flow (atheroprotected) regions such as lesser curvature of the aortic arch and the thoracic aorta, respectively.

Shear stress intimately controls production of both NO and ROS levels in ECs by regulating both enzymes that produce these vasoactive factors as well as those that remove them. By controlling the redox balance in ECs, shear stress plays a critical role in regulating vascular biology and diseases such as inflammation and atherosclerosis. We believe that the combined use of in vitro, ex vivo, and in vivo models described here will provide crucial experimental systems to define the role of oxidative stress and signaling in flow-mediated vascular biology diseases.

Abbreviations Used

ApoE: apolipoprotein E
A/V: arterio-venous
BMP4: bone morphogenetic protein 4
EC: endothelial cell
ECA: external carotid artery
eNOS: endothelial nitric oxide synthase
ICA: internal carotid artery
ICAM-1: inter-cellular adhesion molecule 1
KO: knockout
LCA: left common carotid artery
LS: laminar shear
LSA: left subclavian artery
NO: nitric oxide
Nox: NADPH oxidase
OA: occipital artery
OS: oscillatory shear
PDMS: polydimethylsiloxane
RCA: right common carotid artery
ROS: reactive oxygen species
RSA: right subclavian artery
SMC: smooth muscle cell
SPA: stress phase angle
STA: superior thyroid artery
VCAM-1: vascular cell adhesion molecule 1

Acknowledgments

H.J.'s work was supported by funding from NIH grants HL87012 (H.J.), HL75209 (H.J.), and UO1HL80711 (H.J.) and a World Class University Project (H.J.) from the Ministry of Science, Technology, and Education of South Korea.

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PERMALINK

Animal, In Vitro, and Ex Vivo Models of Flow-Dependent Atherosclerosis: Role of Oxidative Stress

Amir Rezvan

Chih-Wen Ni

Noah Alberts-Grill

Hanjoong Jo

Abstract

Introduction

Animal Models of Atherosclerosis

Hypercholesterolemia-induced atherosclerosis

Arterial injuries inducing atherosclerosis

Animal models of flow-dependent atherosclerosis

Areas of naturally occurring disturbed flow

Models inducing acute changes in shear stress

A/V fistula

Vascular grafts

FIG. 1.

Constrictive perivascular cuff

FIG. 2.

Ligations: complete, incomplete, and partial

Incomplete ligation

Complete ligation

Partial ligation model

FIG. 3.

In Vitro Models for Shear Stress Studies

Cone and plate

FIG. 4.

FIG. 5.

Parallel-plate flow chamber

FIG. 6.

Coculture shear stress system: a modified parallel-plate system

FIG. 7.

Microfluidic devices

FIG. 8.

Other in vitro systems

Simultaneous shear and strain device

Ex Vivo Organ Culture Models

History and background

Ex vivo models of shear-induced oxidative stress

Perspectives

Abbreviations Used

Acknowledgments

References

ACTIONS

PERMALINK

RESOURCES

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