Hypertensive heart disease (HHD) occurs in patients that clinically have both diastolic and systolic heart failure and will soon become the most common cause of heart failure. Two key aspects of heart failure secondary to HHD are the relatively highly prevalent LV hypertrophy and cardiac fibrosis, caused by changes in the local and systemic neurohormonal environment. The fibrotic state is marked by changes in the balance between MMPs and their inhibitors, which alter the composition of the ECM. Importantly, the fibrotic ECM impairs cardiomyocyte function. Recent research suggests that therapies targeting the expression, synthesis, or activation of the enzymes responsible for ECM homeostasis might represent novel opportunities to modify the natural progression of HHD.

Blood vessels are permanently subjected to mechanical forces in the form of stretch, encompassing cyclic mechanical strain due to the pulsatile nature of blood flow and shear stress. Significant variations in mechanical forces, of physiological or physiopathological nature, occur in vivo. These are accompanied by phenotypical modulation of smooth muscle cells and endothelial cells, producing structural modifications of the arterial wall. In all the cases, vascular remodelling can be allotted to a modification of the tensional strain or shear, and underlie a trend to reestablish baseline mechanical conditions. Vascular cells are equipped with numerous receptors that allow them to detect and respond to the mechanical forces generated by pressure and shear stress. The cytoskeleton and other structural components have an established role in mechanotransduction, being able to transmit and modulate tension within the cell via focal adhesion sites, integrins, cellular junctions and the extracellular matrix. Mechanical forces also initiate complex signal transduction cascades, including nuclear factor-jB and mitogen-activated protein kinase pathways, leading to functional changes within the cell.

Blood vessels are exposed to multiple mechanical forces that are exerted on the vessel wall (radial, circumferential and longitudinal forces) or on the endothelial surface (shear stress). The stresses and strains experienced by arteries influence the initiation of atherosclerotic lesions, which develop at regions of arteries that are exposed to complex blood flow. In addition, plaque progression and eventually plaque rupture is influenced by a complex interaction between biological and mechanical factors-mechanical forces regulate the cellular and molecular composition of plaques and, conversely, the composition of plaques determines their ability to withstand mechanical load. A deeper understanding of these interactions is essential for designing new therapeutic strategies to prevent lesion development and promote plaque stabilization. Moreover, integrating clinical imaging techniques with finite element modelling techniques allows for detailed examination of local morphological and biomechanical characteristics of atherosclerotic lesions that may be of help in prediction of future events. In this ESC Position Paper on biomechanical factors in atherosclerosis, we summarize the current 'state of the art' on the interface between mechanical forces and atherosclerotic plaque biology and identify potential clinical applications and key questions for future research.

Abstract-Tears in the internal elastic lamina (IEL) can be observed after chronic increases in arterial blood flow, suggesting a potential role for matrix metalloproteinases (MMPs) in flow-induced vascular remodeling. We undertook to study this phenomenon by constructing an arteriovenous fistula (AVF) between the left common carotid artery (CCA) and the external jugular vein in rabbits. The diameter of the flow-loaded left CCA increased by 13.6Ϯ1.8% by day 3 after construction of the AVF compared with the right CCA (nϭ4, PϽ0.01) and by 40.7Ϯ7.5% by day-15 (nϭ10, PϽ0.0001). Increased CCA diameter also coincided with IEL fragmentation. Three days after construction of the AVF, gelatin zymography of protein extracts from left CCAs of untreated rabbits showed a significant increase in the 62-kDa (active MMP-2) activity and the appearance of a lytic band at 92 kDa (pro-MMP-9). In further experiments, MMP activity was inhibited by treatment with doxycycline (DOX) or BB-94, a specific MMP inhibitor. The increase in the 62-kDa gelatinolytic band was abolished in DOX-and BB-94 -treated rabbits. The 92-kDa gelatinolytic band was also reduced in DOX-treated animals. Furthermore, both increased left CCA diameter and IEL fragmentation were abolished in DOX-and BB-94 -treated rabbits. To evaluate whether nitric oxide was involved in blood flow-induced MMP activation, the rabbits were treated with N G -nitro-L-arginine methyl ester to inhibit nitric oxide synthesis. MMP activities were significantly decreased in the left CCAs of Key Words: wall shear stress Ⅲ vascular remodeling Ⅲ matrix metalloproteinases C hronic increases in arterial blood flow elicit an adaptive response of the arterial wall, characterized by the reorganization of cellular and extracellular components and leading to arterial enlargement and a reduction in wall shear stress (WSS) to physiological baseline values. [1][2][3][4] There is evidence that the endothelium plays an essential role in this adaptive process. 3,5 In models of arteriovenous fistula (AVF), endothelial denudation abolishes arterial diameter growth, 3 and we have shown that chronic inhibition of nitric oxide (NO) production by N G -nitro-L-arginine methyl ester (L-NAME) treatment inhibits, at least partially, the adaptive WSS regulation in flow-loaded vessels. 4 However, the mechanisms by which the endothelium or endothelium-dependent NO operates to induce arterial wall remodeling are not understood. Interestingly, disruption of the extracellular matrix with tears of the internal elastic lamina (IEL) can be observed in this model, which suggests a potential role for matrix metalloproteinases (MMPs) in matrix digestion and reorganization, leading to arterial wall remodeling, 4,6 -11 and for NO in MMP activation. 12 This study was therefore designed to examine the effects of chronic in vivo inhibition of MMPs by treatment with BB-94, a specific MMP inhibitor, or doxycycline (DOX), on vascular remodeling of the common carotid artery (CCA) in a rabbit model of AVF. We also evaluated the effect...

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Rationale and Objective: Membrane-shed submicron microparticles (MPs) released following cell activation or apoptosis accumulate in atherosclerotic plaques, where they stimulate endothelial proliferation and neovessel formation. The aim of the study was to assess whether or not MPs isolated from human atherosclerotic plaques contribute to increased endothelial adhesion molecules expression and monocyte recruitment. Method and Results:Human umbilical vein and coronary artery endothelial cells were exposed to MPs isolated from endarterectomy specimens (n‫)26؍‬ and characterized by externalized phosphatidylserine. Endothelial exposure to plaque, but not circulating, MPs increased ICAM-1 levels in a concentration-dependant manner (3.4-fold increase) without affecting ICAM-1 mRNA levels. Plaque MPs harbored ICAM-1 and transferred this adhesion molecule to endothelial cell membrane in a phosphatidylserine-dependent manner. MP-borne ICAM-1 was functionally integrated into cell membrane as demonstrated by the increased ERK1/2 phosphorylation following ICAM-1 ligation. Plaque MPs stimulated endothelial monocyte adhesion both in culture and in isolated perfused mouse carotid. This effect was also observed under flow condition and was prevented by anti-LFA-1 and anti-ICAM-1 neutralizing antibodies. MPs isolated from symptomatic plaques were more potent in stimulating monocyte adhesion than MPs from asymptomatic patients. Plaque MPs did not affect the release of interleukin-6, interleukin-8, or MCP-1, nor the expression of VCAM-1 and E-selectin. Key Words: microparticle Ⅲ ICAM-1 Ⅲ adhesion Ⅲ monocyte Ⅲ microvesicle A therosclerosis is a chronic inflammatory disease characterized by the accumulation of leukocytes, lipids, and fibrous tissue in the intima of arteries. 1 In atherosclerotic plaques, endothelial cells express elevated amounts of adhesion molecules such as selectins (P-selectin and E-selectin) and intercellular (ICAM-1) and vascular (VCAM-1) adhesion molecules at their surface. 1,2 Cytokines and chemokines are also secreted in excess by activated vascular cells in this context. These conditions favor the recruitment and the accumulation of monocytes and lymphocytes in the intima of vessels. 1,2 Human atherosclerotic plaques contain large amounts of microparticles (MPs), which are submicron membrane vesicles released following cell activation or apoptosis. [3][4][5] MPs harbor at their surface most of the membrane-associated proteins of the cells they stem from and are characterized by the loss of plasma membrane asymmetry resulting in the exposure of phosphatidylserine on their outer leaflet. 6,7 MPs isolated from human atherosclerotic lesions are highly thrombogenic and originate from multiple cells, including macrophages, lymphocytes, erythrocytes, and smooth muscle and endothelial cells. 4,5 MPs are no longer taken as innocent bystanders because several studies point out that MPs generated in vitro from cultured cells can affect several cellular functions, including inflammatory responses. 8 -15 However,...

Abstract-Chronic alterations in blood flow elicit an adaptive response that tends to normalize shear stress, involving nitric oxide (NO) and matrix metalloproteinases (MMPs). To evaluate the role of NADPH oxidase in this process, we developed a new model of mouse arteriovenous fistula (AVF) connecting the right common carotid artery (RCCA) with the jugular vein, which does not affect blood pressure. Mice deficient for gp91phox and p47phox subunits of NADPH and wild-type controls were used. AVF greatly increased RCCA blood flow (0.78Ϯ0.12 to 4.71Ϯ0.78 mL/min; PϽ0.01), producing an abrupt rise in shear stress (35Ϯ1 to 261Ϯ17 dynes/cm 2 ; PϽ0.01) within 24 hours. RCCA diameter (460Ϯ14 m) gradually enlarged 1 and 3 weeks after AVF (534Ϯ14 m and 627Ϯ19 m; PϽ0.01), reducing shear stress (173Ϯ13 and 106Ϯ10 dynes/cm 2 , respectively). In gp91phox Ϫ/Ϫ mice, changes in RCCA caliber and shear stress matched controls. However, p47phoxϪ/Ϫ mouse RCCAs enlarged only marginally, such that shear stress remained high (199Ϯ8 dynes/cm 2 at 3 weeks). Likewise, remodeling was minimal in endothelial NO synthase (eNOS) Ϫ/Ϫ mice. In both control and gp91phox Ϫ/Ϫ animals, reactive oxygen species (ROS) production and MMP induction was enhanced by AVF, whereas in p47phox Ϫ/Ϫ and eNOS Ϫ/Ϫ mice such response was negligible. Similarly, nitrotyrosine staining, indicating peroxynitrite formation, was more pronounced in control and gp91phoxϪ/Ϫ mice than in p47phox Ϫ/Ϫ and eNOS Ϫ/Ϫ mice. Hence, shear stress induces vascular NADPH oxidase comprising p47phox but not gp91phox. Generated ROS interact with NO to produce peroxynitrite, which in turn activates MMPs, facilitating vessel remodeling. Our study provides the first evidence that ROS play a fundamental role in flow-induced vascular enlargement. (Circ Res. 2005;97:533-540.)Key Words: extracellular matrix Ⅲ metalloproteinases Ⅲ reactive oxygen species Ⅲ shear stress C hanges in blood flow drive both acute and long-term compensatory responses in the vascular wall that tend to normalize wall shear stress. In the case of persistent increases in flow, adaptive remodeling of the vessel involves the reorganization of cellular and extracellular components. This is best exemplified in models of arteriovenous fistula (AVF), where steep increases in flow result in extensive arterial enlargement through restructuring of the extracellular matrix and modulation of vascular cell synthetic capacity. 1 One of the striking characteristics of the arterial wall proximal to an AVF is extensive tearing and fragmentation of the internal elastic lamina (IEL) 2,3 which augments arterial distensibility, leading to enhanced vessel diameter. Matrix metalloproteinases (MMPs) are likely instigators of IEL degradation in the vessel wall. MMP-2 and MMP-9 are upregulated shortly after AVF construction, and heightened activity of these enzymes persists until shear stress is normalized. 4,5 Furthermore, several studies have reported that MMP inhibition diminishes flow-mediated arterial enlargement in rat 4,6 and rabbit 5 AVF mod...

Abstract-The vascular wall is constantly subjected to a variety of mechanical forces in the form of stretch (tensile stress), due to blood pressure, and shear stress, due to blood flow. Alterations in either of these stresses are known to result in vascular remodeling, an adaptation characterized by modified morphology and function of the blood vessels, allowing the vessels to cope with physiological or pathological conditions. The processes involved in vascular remodeling include cellular hypertrophy and hyperplasia, as well as enhanced protein synthesis or extracellular matrix protein reorganization. In vitro studies using vascular cells have attempted to identify the mechanisms behind structural alterations. Possible pathways include ion channels, integrin interaction between cells and the extracellular matrix, activation of various tyrosine kinases (such as c-Src, focal adhesion kinase, and mitogen-activated protein kinases), and autocrine production and release of growth factors. These pathways lie upstream of de novo synthesis of immediate response genes and total protein synthesis, both of which are likely to be involved in the process of vascular remodeling.(Hypertension. 1998;32:338-345.)Key Words: shear stress Ⅲ stretch Ⅲ muscle, smooth Ⅲ endothelium Ⅲ MAP kinases B lood vessels are permanently subjected to mechanical forces in the form of stretch, which because of the pulsatile nature of blood flow exposes vessels to cyclic mechanical strain, and shear stress. Blood pressure is the major determinant of vessel stretch. It creates radial and tangential forces that counteract the effects of intraluminal pressure and that affect all cell types in the vessel. In comparison, fluid shear stress results from the friction of blood against the vessel wall, and it acts in parallel to the vessel surface. Accordingly, shear is sensed principally by endothelial cells, strategically located at the interface between the blood and the vessel wall. Alterations in stretch or shear stress invariably produce transformations in the vessel wall that will aim to accommodate the new conditions and ultimately restore basal levels of tensile stress and shear stress.1-3 Hence, while acute changes in stretch or shear stress correlate with transient adjustments in vessel diameter, mediated through release of vasoactive agonists or change in myogenic tone, chronically altered mechanical forces usually instigate important adaptive alterations of vessel wall shape and composition. The concept of vascular remodeling has therefore been used to describe the transformations that occur in vessels undergoing mechanical stresses. For example, experimental hypertension is accompanied by increased wall thickness, resulting in resistance arteries and arterioles from VSMC hyperplasia and in conductance arteries from hypertrophy. 4,5 Likewise, reduced mechanical strain translates into vessel atrophy.Several reports describe the effects of mechanical stretch on hypertrophy of the heart, and the pathways leading to these events have been studied e...