doi: 10.1161/CIRCULATIONAHA.106.634378
(Circulation. 2006;113:2787-2789.)
© 2006 American Heart Association, Inc.
Editorial |
Shear Stress–Mediated Arterial Remodeling in Atherosclerosis
Too Much of a Good Thing?
From the Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Mass.
Correspondence to Joseph A. Vita, MD, Section of Cardiology, Boston Medical Center, 88 E Newton St, Boston, MA, 02118. E-mail jvita{at}bu.edu
Key Words: Editorials • atherosclerosis • blood flow • endothelium • imaging • remodeling
Under physiological conditions, chronic changes in blood flow stimulate compensatory changes in arterial size. This arterial remodeling process occurs during normal growth and development and contributes to the adaptive response to a variety of clinical situations. For example, repetitive increases in blood flow during exercise may stimulate expansive remodeling of conduit arteries in the limbs and heart,1 whereas chronic disuse of the lower extremities as a result of spinal cord injury is associated with constrictive remodeling of the femoral arteries.2 Uterine arteries display expansive remodeling during pregnancy and then undergo constrictive remodeling after delivery. Thus, dynamic remodeling of the arterial tree plays a critical role in maintaining the appropriate balance between tissue demand and blood supply throughout life.
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A primary signal for arterial remodeling is shear stress, which is the frictional force at the endothelial surface produced by flowing blood.3,4 Shear stress relates directly to flow and blood viscosity and inversely to the third power of arterial radius.3 A macroscopic increase in blood flow increases local shear stress and stimulates arterial expansion until shear stress has been restored to baseline. Conversely, low shear stress leads to constrictive remodeling. This important homeostatic mechanism maintains shear stress in an appropriate range. When exposed to physiological levels of shear stress (15 to 40 dyne/cm2), endothelial cells appropriately elongate, align in the direction of flow, and maintain barrier function.4 Furthermore, normal shear stress promotes expression of vasodilator and antithrombotic factors, suppresses growth and proinflammatory factors, and generally maintains a state of vascular health. In contrast, low, oscillating, and disordered shear stress promotes the development of atherosclerosis.
Expansive remodeling in response to chronic or repetitive increases in flow involves a coordinated sequence of events in the arterial wall, as has been extensively reviewed.3,5,6 Over a period of days, endothelial cells swell and proliferate. Nuclear factor-
B (NFB) is activated and endothelial cells express adhesion molecules and chemotactic factors, leading to accumulation of inflammatory cells. This local inflammatory response induces phenotypic changes in vascular smooth muscle cells and fibroblasts, increases expression of matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, and decreases expression of tissue inhibitors of metalloproteinases. Increased collagen turnover and marked changes in arterial architecture, including the development of gaps and redundancy in the internal elastic lamina, result. Local expression of growth factors such as transforming growth factor-ß and platelet-derived growth factor and colony-stimulating factors contribute to the proliferation and migration of vascular smooth muscle cells. The result is an enlarged arterial lumen with a proportional increase in wall thickness.
Several recent reviews have outlined the complex molecular mechanisms accounting for the endothelial response to shear stress.4,5,7,8 Shear stress activates a variety of signaling pathways, including the phosphatidylinositol-3 kinase/Akt signaling system in endothelial cells, leading to activation of endothelial nitric oxide synthase. Interestingly, both expansive and constrictive remodeling is prevented by blockade or knockout of endothelial nitric oxide synthase. Shear stress activates a number of other signaling pathways, including the mitogen-activated kinases and protein kinase C. Transduction of the mechanical forces produced by flowing blood into biochemical signals involves deformation of cell surface proteins, and proposed mechanotransducers include integrins, membrane microdomains, ion channels, vascular endothelial growth factor receptor-2, VE-cadherin, and platelet endothelial cell adhesion molecule-1. As recently reviewed, small GTPases, including Rac1, Cdc42, and RhoA, are important regulators of the endothelial response to shear stress. For example, expansive remodeling involves activation of Rho/Rho kinase, whereas flow reduction and inward remodeling are associated with downregulation of this system. Overall, arterial remodeling appears to represent a coordinated stress response with controlled and transient activation of proinflammatory signaling pathways.6
Arterial remodeling is highly relevant to the process of atherosclerosis. As first described by Glagov and colleagues,9 expansive remodeling is a compensatory mechanism that maintains coronary arterial lumen size until plaques occupy &40% of the vessel cross-sectional area. This mechanism may account for the observation that atherosclerosis often remains silent for decades before producing symptoms and for the well-recognized limitations of angiography as a predictor of atherosclerosis extent. Pathological studies also suggest a relationship between plaque composition and the degree of expansive or constrictive remodeling.10 Greater expansive remodeling was observed in plaques with evidence of macrophage accumulation, plaque hemorrhage, a larger lipid core, and thinner fibrous cap, features associated with vulnerability to rupture. In contrast, constrictive remodeling was associated with more fibrotic and presumably more stable plaques that nevertheless can produce effort angina. In support of this contention, patients with acute coronary syndromes were more likely to display expansive remodeling of the culprit coronary lesion.11
Both experimental and human studies have examined the relations between cardiovascular disease risk factors and arterial remodeling.12,13 In regard to dyslipidemia, atherosclerotic lesion development is associated with expansive remodeling in hypercholesterolemic monkeys and pigs and in apolipoprotein E–deficient mice. In some situations, lumen area may exceed that of control animals, suggesting that the remodeling process can actually "overcompensate" for the enlarging plaque, a finding also described in human autopsy studies.9 In human studies using intravascular ultrasound, hypercholesterolemia is associated with expansive remodeling at the site of coronary artery lesions, whereas cigarette smoking, diabetes mellitus, and hypertension are more commonly associated with constrictive remodeling.
It is well established that lipid-lowering therapy slows plaque progression, alters histological features of atherosclerotic lesions, and reduces cardiovascular events. In general, a reduction in serum cholesterol by diet or drugs is associated with a reduction in vascular inflammation and lesion lipid content and a shift toward a more fibrotic and presumably more stable lesion. Recently, there has been interest in the possibility that lipid-lowering therapy might influence the remodeling process. For example, in a serial examination of arterial architecture by magnetic resonance imaging, Corti and colleagues14 reported that lipid-lowering therapy was associated with constrictive remodeling of the aorta and carotid arteries. This finding remains controversial, however, because some studies failed to demonstrate such an effect.15
In this issue of Circulation, Schoenhagen and colleagues16 provide further information about the effects of lipid-lowering therapy on arterial remodeling in a prospectively planned substudy of the REVERSAL trial. REVERSAL was a multicenter, randomized trial comparing the effects of "intensive" and "moderate" lipid-lowering therapy for 18 months on volume of coronary atherosclerotic plaque as assessed by intravascular ultrasound in 502 patients.17 In the main study, intensive lipid-lowering therapy was associated with less atherosclerosis progression. The substudy assessed arterial remodeling in a subset of 210 patients with an identifiable focal lesion. The authors measured lumen and external elastic lamina areas within the lesion and in a normal or nearly normal proximal reference segment. They calculated plaque area and percent plaque burden in the lesion and the "remodeling ratio," which is the ratio of the external elastic lamina areas in the lesion and reference segments, respectively.18 A remodeling ratio >1 indicates that the vessel cross-sectional area is larger at the lesion compared with the reference segment and is consistent with expansive remodeling. Overall, the authors observed that the external elastic lamina area, lumen area, and plaque area were all greater at follow-up compared with baseline, reflecting modest progression of atherosclerosis and expansion of the artery at the lesion site. However, there was a mean 3% decrease in remodeling ratio, reflecting less vessel expansion at the lesion site compared with the reference site and suggesting relative constrictive remodeling. In a multivariable analysis, vessels with greater progression of atherosclerosis, those with evidence of expansive remodeling at baseline, and patients with increased C-reactive protein during treatment had a larger remodeling ratio at the follow-up study. Notably, changes in cholesterol levels and treatment assignment did not correlate with expansive remodeling.
Strengths of this study include the longitudinal design, relatively large sample size, and conduct of the study in the setting of a well-controlled clinical trial. Furthermore, a highly experienced group conducted the study and analyzed the results. Despite these strengths, however, the findings must be interpreted with some caution. When considering the absolute changes in arterial architecture over time, the study demonstrated expansive remodeling and progression of atheroma volume for the group as a whole. Strictly speaking, the results could be interpreted as evidence that statin treatment causes expansive remodeling. The authors’ conclusion that statin therapy has the opposite effect is based solely on the change in remodeling ratio, which is recognized to be an indirect measure of remodeling that depends on the behavior of a reference segment that is unlikely to be truly normal.18 Furthermore, as the authors acknowledge, the remodeling ratio has only modest reproducibility and is limited by consideration of the area of 2D "slices" rather than the volume of plaque in the lesion and reference segments. Design of the multivariable analysis is an issue because it examined predictors of the remodeling ratio only at the follow-up visit. The conclusions would have been more convincing if this analysis had examined the clinical predictors of actual change in vessel area at the lesion. All patients in the study received statin therapy, and the inclusion of a placebo group would have provided a better understanding of the biology of arterial remodeling. Finally, the lack of a detectable difference between the "intensive" and "moderate" lipid-lowering groups may raise questions about the clinical significance of the findings, given the well-established benefit of more aggressive lipid-lowering therapy in regard to cardiovascular events.
Despite the limitations of the study, the finding that C-reactive protein levels predicted expansive remodeling is consistent with prior experimental and human autopsy studies linking inflammation to the remodeling process. It is interesting to speculate that the "controlled" inflammatory response that accounts for appropriate arterial remodeling might become "uncontrolled" under the proinflammatory conditions associated with atherosclerosis and lead to excessive expansive remodeling and contribute to plaque vulnerability. Another interesting area for speculation is the link between statin therapy and specific mechanisms related to the remodeling process. For example, both lipid-lowering diet and statin therapy reduce the expression of MMPs in the arterial wall,19 and theoretically, these interventions could limit expansive remodeling. By inhibiting production of the cholesterol intermediate geranylgeranyl pyrophosphate, statin treatment also inhibits intracellular trafficking required for activation of the Rho/Rho kinase system,20 and this effect would be expected to inhibit expansive remodeling.8 Additional studies using more specific inhibitors of the Rho/Rho kinase pathway are required to address this question.
In summary, arterial remodeling is an important adaptive response to changes in flow and local shear stress. Experimental studies have begun to elucidate the mechanisms that regulate this process and point to a controlled and self-limited inflammatory response in the vessel wall. In the setting of atherosclerosis, expansive remodeling may initially be an adaptive response that compensates for lumen obstruction. There is growing evidence, however, that inappropriate expansive remodeling and associated inflammatory responses in the arterial wall might contribute to plaque vulnerability. Further studies are needed to better define operative mechanisms in humans, the relationship of expansive remodeling to cardiovascular events, and the implications of these findings for therapy of patients with coronary artery disease.
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Acknowledgments |
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Sources of Funding
Dr Silver is supported by National Institutes of Health training grant T32 HL 07224. Dr Vita is supported by grants from the National Institutes of Health (R01 HL75795, P01 HL081587, P50 HL083801, and R01HL083269). Dr Vita also receives research support from Abbott Pharmaceuticals.
Disclosures
Dr Vita serves as a speaker for Pfizer, Inc, and Merck, Inc. Dr Silver reports no conflicts.
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Footnotes |
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The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
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