It’s All About the Stress
Abdominal aortic aneurysms (AAAs) are present in 8% of men >60 years of age.1 The diagnosis of AAA in many patients is made only after aneurysm rupture, after which mortality is high. Depending on the size of the AAA, often times the only treatment available after its discovery is “watchful waiting.” Although aneurysm diameter is generally used to assess timing of surgical repair, rupture also occurs in AAAs less than 5 cm in diameter.2 The absence of effective medical therapy for AAA is explained in part by a poor understanding of the processes involved in the development of aneurysms. Treatment that could slow AAA growth would have important therapeutic value.
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An emerging concept is that AAAs develop in the setting of oxidative stress, whereby reactive oxygen species (ROS) mediate activation of matrix degrading proteins and smooth muscle cell apoptosis, resulting in loss of medial elastic lamellae and thinning of the tunica media. This concept is supported by the observations that infiltration of inflammatory cells into the vessel wall and subsequent elaboration of matrix metalloproteinases (MMPs) are associated with formation of AAAs. ROS are abundantly produced by inflammatory cells and activate MMPs.3 And, in humans, ROS levels and oxidative injury are greater in AAAs compared with adjacent nonaneurysmal aortic segments.4
Mechanical forces also contribute to aortic remodeling. The artery wall is subject to three distinct fluid-induced forces: (1) pressure created by hydrostatic forces, (2) circumferential stretch exerting longitudinal forces, and (3) shear stress created by the movement of blood. The net force includes a component perpendicular to the wall, the pressure, and a component along the wall, the shear stress. Disturbed flow conditions, such as turbulence, contribute to aneurysm growth by causing injury to the endothelium and accelerating degeneration of the arterial wall. Areas of flow oscillation and extremes in shear stress (high or low) correlate with development of atherosclerosis in aorta.5 Although clinical studies show that flow within AAAs can be smooth and laminar or irregular and turbulent,6 little information is available on effects of wall shear stress in aneurysms.
In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Nakahashi and colleagues7 report that an increase in aortic wall shear stress and relative wall strain, generated by creation of a femoral arteriovenous fistula, preserved the tunica media and slowed aortic dilation in experimental AAAs. The increase in shear stress was associated with a reduction in ROS. The flow-mediated increase in shear stress did not decrease oxidative stress in AAAs by reducing the inflammatory cell infiltrate. Instead, flow loading of AAAs increased expression of heme oxygenase (HO-1) in macrophages. Activation of HO-1 expression is an adaptive cellular response to survive exposure to environmental stresses.8 HO-1 has anti-inflammatory effects and may have a beneficial role in reducing oxidative reactions through the production of the antioxidants biliverdin and bilirubin.9
Through poorly understood mechanisms of mechanoreception, vascular cells sense and respond to shear stress. In this way, mechanical forces can increase or decrease gene activation in the blood vessel wall. For example, laminar shear stress increases expression of superoxide dismutase and endothelial nitric oxide synthase in cultured human endothelial cells, whereas turbulent shear stress does not induce these protective genes.10 Mechanically induced genes contain positive and negative shear stress responsive elements in their promoter regions, such as antioxidant response element (ARE), that functions to protect cells against oxidant stress. Laminar flow activates HO-1 expression by ARE-mediated transcriptional activity in endothelial cells.11
Given the beneficial effects of flow loading on vessel remodeling in AAA, it may be surprising that shear stress did not reduce expression of MMP-2 or MMP-9. However, because ROS activate latent proforms of MMPs in the vascular interstitium,3 reduction in oxidative stress may have nonetheless resulted in decreased MMP activity.
Because of limitations in studying hemodynamics in vivo, in vitro models of AAAs have often been used to analyze pressure and flow patterns. However, these biomechanical designs often use an axisymmetric model, whereas AAAs, particularly in advanced stages, are asymmetric, resulting in growth away from the lumen’s centerline. Interpretation of mechanical models can also be limited if they neglect effects of branch arteries, or by their use of steady flow, rigid walls, and homogenous and incompressible fluid. Understanding the biology of AAA development and expansion requires experiments in animal models. Unfortunately, in vivo studies are complicated by controversy regarding the appropriate animal model of human AAAs. The elastase infusion model used by Nakahashi et al7 differs from other models of AAA in the mechanism and magnitude of elastin degradation and inflammatory infiltrate. As an alternative model, it has recently been described that angiotensin-II infusion induces AAAs in hypercholesterolemic mice.12 Because angiotensin-II increases vascular ROS, this model also suggests a causative role of oxidative stress in the development of AAA. It will need to be determined if the findings of Nakahashi et al7 are unique to the elastase model of AAA.
AAAs join a long list of vascular diseases associated with increased oxidative stress. Although the potential effects of ROS in the vessel wall are numerous, the specific role of oxidative stress in the pathogenesis of vascular disease is less clear. In addition to the effects of flow loading, Nakahashi and colleagues7 show that α-tocopherol supplementation reduces ROS levels and the size of AAAs in the elastase infusion model. The protective effect of α-tocopherol on AAA expansion is reason for optimism in the treatment of AAAs, but it is also consistent with other animal studies showing antioxidants protect from vascular disease. Randomized clinical trials, however, have routinely failed to convert the protective findings of antioxidants in animal studies to humans.13 Subgroup analysis of the α-Tocopherol, β-Carotene Cancer Prevention (ATBC) Study found that α-tocopherol supplementation did not decrease the risk of AAAs in men.14 However, the low dose of α-tocopherol (50 mg/d) and the identification of only those patients with large AAAs make this negative study difficult to interpret.
The development of AAAs in humans is not predicted solely by the severity of atherosclerosis or by the presence of specific risk factors. Instead, susceptibility to AAAs may depend on the adaptive expression of protective genes in response to oxidative stress or other inflammatory stimuli. Recently, a polymorphism in the HO-1 promoter has been linked to levels of HO-1 transcription and, interestingly, to patients with AAAs.15
With more and more evidence supporting a role for oxidative stress in vascular disease and the general failure of antioxidants in clinical trials, it is important to identify novel approaches that decrease oxidative stress in the blood vessel. As described by Nakahashi et al,7 flow loading reduces oxidative stress in AAAs.7 Activation of genes via shear stress responsive elements may represent an antioxidant and anti-inflammatory mechanism in the vasculature. Interventions successful in reducing oxidative stress in the vessel wall have the potential to change the progression of many vascular diseases.
- ↵Rajagopalan S, Meng XP, Ramasamy S, Harrison DG, Galis ZS. Reactive oxygen species produced by macrophage-derived foam cells regulate the activity of vascular matrix metalloproteinases in vitro: implications for atherosclerotic plaque stability. J Clin Invest. 1996; 98: 2572–2579.
- ↵Miller FJ Jr, Sharp WJ, Fang X, Oberley LW, Oberley TD, Weintraub NL. Oxidative stress in human abdominal aortic aneurysms: a potential mediator of aneurysmal remodeling. Arterioscler Thromb Vasc Biol. 2002; 22: 560–565.
- ↵Ku DN, Giddens DP, Zarins CK, Glagov S. Pulsatile flow and atherosclerosis in the human carotid bifurcation: positive correlation between plaque location and low oscillating shear stress. Arteriosclerosis. 1985; 5: 293–302.
- ↵Nakahashi TK, Hoshina K, Tsao PS, Sho E, Sho M, Karwowski JK, Yeh C, Yang R-B, Topper JN, Dalman RL. Flow loading induces macrophage antioxidative gene expression in experimental aneurysms. Arterioscler Thromb Vasc Biol. 2002; 22: 2017–2022.
- ↵Topper JN, Cai J, Falb D, Gimbrone MA Jr. Identification of vascular endothelial genes differentially responsive to fluid mechanical stimuli: cyclooxygenase-2, manganese superoxide dismutase, and endothelial cell nitric oxide synthase are selectively up-regulated by steady laminar shear stress. Proc Natl Acad Sci U S A. 1996; 93: 10417–10422.
- ↵Chen XL, Varner SE, Rao AS, Grey JY, Thomas S, Cook CK, Wasserman MA, Medford RM, Jaiswal AK, Kunsch C. Laminar shear stress induction of antioxidant response element-mediated genes in endothelial cells: a novel anti-inflammatory mechanism. J Biol Chem. 2002;(epub ahead of print). Available at www.jbc.org. Last accessed November 15, 2002.
- ↵Asplund K. Antioxidant vitamins in the prevention of cardiovascular disease: a systematic review. J Intern Rev. 2002; 251: 372–392.