Biomechanical factors in atherosclerosis: mechanisms and clinical implications†

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 researc

Bases cellulaires de la mécanotransduction dans la cellule endothéliale

Les vaisseaux sanguins sont en permanence soumis à des contraintes mécaniques associées à la pression artérielle, de caractère pulsé, et au flux sanguin. Toute variation de ces contraintes est perçue au niveau des cellules vasculaires et se traduit par des modifications fonctionnelles et structurales des vaisseaux. De nombreux récepteurs, présents à la surface des cellules endothéliales, sont sensibles aux forces de cisaillement. Les intégrines, reliant la matrice extracellulaire aux sites d’adhérence focale et au cytosquelette, peuvent transmettre et moduler la tension mécanique dans la cellule. Par ailleurs, les contraintes mécaniques agissent sur les canaux ioniques, stimulant des récepteurs membranaires et induisent des cascades complexes d’événements biochimiques. De nombreuses voies intracellulaires, telles que la voie des MAP-kinases, sont actives par le flux sanguin et aboutissent à l’induction de facteurs de transcription qui contrôlent l’expression des gènes. Ainsi, par des mécanismes purement locaux, le vaisseau sanguin est capable de s’adapter à son environnement mécanique

Shear stress, arterial identity and atherosclerosis

In the developing embryo, the vasculature first takes the form of a web-like network called the vascular plexus. Arterial and venous differentiation is subsequently guided by the specific expression of genes in the endothelial cells that provide spatial and temporal cues for development. Notch1/4, Notch ligand delta-like 4 (Dll4), and Notch downstream effectors are typically expressed in arterial cells along with EphrinB2, whereas chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) and EphB4 characterise vein endothelial cells. Haemodynamic forces (blood pressure and blood flow) also contribute importantly to vascular remodelling. Early arteriovenous differentiation and local blood flow may hold the key to future inflammatory diseases. Indeed, despite the fact that atherosclerosis risk factors such as smoking, hypertension, hypercholesterolaemia, and diabetes all induce endothelial cell dysfunction throughout the vasculature, plaques develop only in arteries, and they localise essentially in vessel branch points, curvatures and bifurcations, where blood flow (and consequently shear stress) is low or oscillatory. Arterial segments exposed to high blood flow (and high laminar shear stress) tend to remain plaque-free. These observations have led many to investigate what particular properties of arterial or venous endothelial cells confer susceptibility or protection from plaque formation, and how that might interact with a particular shear stress environment

Metalloproteinases, mechanical factors and vascular remodeling

Chronic increases in arterial blood flow elicit an adaptive response of the arterial wall, leading to vessel enlargement and reduction in wall shear stress to physiological baseline value. Release of nitric oxide from endothelial cells exposed to excessive shear is a fundamental step in the remodeling process, and potentially triggers a cascade of events, including growth factor induction and matrix metalloproteinase activation, that together contribute to restructuralization of the vessel wall. NO synthesis blockade in vivo inhibits adaptive wall shear stress regulation in vessels subjected to chronic increased blood flow. This effect is partial, indicative that other factors are probably involved. The pathways by which the remodeling action of NO is mediated include metalloproteinase activation and possibly implicate the induction of growth factor mitogenic activity as well. Furthermore, matrix metalloproteinase (MMP) activation is required for adaptive arterial remodeling (IEL fragmentation and arterial enlargement) to occur. These observations are significant since adaptive vascular enlargement and remodeling are known to accompany early human coronary atherosclerosis, and exaggerated expression of MMPs, in particular MMP-2, is now known to be a ubiquitous marker of aortic aneurysms, and could reflect abnormal flow-induced vessel remodeling. Hence understanding the process of vascular remodeling could help explain how changes in blood vessel wall structure occur in the context of atherosclerosis or aortic aneurisms.Powerpoint presentation available in PDF format onl

The Multifaceted Uses and Therapeutic Advantages of Nanoparticles for Atherosclerosis Research

Nanoparticles are uniquely suited for the study and development of potential therapies against atherosclerosis by virtue of their size, fine-tunable properties, and ability to incorporate therapies and/or imaging modalities. Furthermore, nanoparticles can be specifically targeted to the atherosclerotic plaque, evading off-target effects and/or associated cytotoxicity. There has been a wealth of knowledge available concerning the use of nanotechnologies in cardiovascular disease and atherosclerosis, in particular in animal models, but with a major focus on imaging agents. In fact, roughly 60% of articles from an initial search for this review included examples of imaging applications of nanoparticles. Thus, this review focuses on experimental therapy interventions applied to and observed in animal models. Particular emphasis is placed on how nanoparticle materials and properties allow researchers to learn a great deal about atherosclerosis. The objective of this review was to provide an update for nanoparticle use in imaging and drug delivery studies and to illustrate how nanoparticles can be used for sensing and modelling, for studying fundamental biological mechanisms, and for the delivery of biotherapeutics such as proteins, peptides, nucleic acids, and even cells all with the goal of attenuating atherosclerosis. Furthermore, the various atherosclerosis processes targeted mainly for imaging studies have been summarized in the hopes of inspiring new and exciting targeted therapeutic and/or imaging strategies