Vascular Endothelium, Hemodynamic Forces, and Atherogenesis

Abstract

Intimal lipid accumulation, hyperplasia, and scarring are stigmata of atherosclerotic vascular disease, whose major complications-myocardial and cerebral ischemia and infarction-continue to be major health problems in developed nations. 1 This insidiously progressive disease typically spans decades, but can reach a clinical horizon in a matter of minutes due to critical changes in a given atherosclerotic plaque that result in localized but lifethreatening thrombosis. Epidemiological studies have established that hypercholesterolemia is an important risk factor in this disease process, and lipid-lowering drugs have been proven to have clinical efficacy. Experimental animals that are fed lipid-rich diets to elevate their plasma cholesterol levels also can develop atherosclerotic-like lesions, as do animals with naturally occurring or genetically engineered mutations that result in altered cholesterol metabolism. However, regardless of a given patient's risk factor profile, species of animal model, or type of natural or engineered genetic alteration, the early, lipid-rich lesions of atherosclerosis show a markedly nonrandom pattern of distribution within the arterial vasculature. Atherosclerotic lesions typically develop in the vicinity of branch points and areas of major curvature. These arterial geometries are associated with blood flow disturbances such as nonuniform laminar flow with boundary layer separation, complex secondary flows with flow reversal and dynamic stagnation points, and resultant temporal and spatial gradients in wall shear stresses. In contrast to these atherosclerosis-prone areas, unbranched, tubular arterial geometries, which are associated with a more uniformly laminar flow profile, characteristically are relatively atherosclerosis-resistant, at least in the early phases of the disease. This strikingly localized pattern of lesion formation, even in the face of systemic risk factors such as elevated plasma cholesterol, has intrigued experimental pathologists and fluid mechanical engineers alike for decades, and has motivated the search for a mechanistic link between hemodynamic forces and atherogenesis.In this issue of The American Journal of Pathology, Zand and coworkers 2 describe a novel experimental model system for creating flow disturbances in the aorta of the rat that have significant effects on the pattern of intimal lipid deposition induced by chronic dietary hypercholesterolemia. Surgical insertion of a hemispherical glass plug into the aortic lumen, through the ostium of a severed renal artery, created a significant stenosis (greater than 50% cross-sectional area reduction) without causing any compression of the adjacent aortic wall, as typically occurs in other models involving an externally applied ligature or metal clip. This model thus accomplishes two useful things: it reliably creates an altered vascular geometry designed to induce well characterized intraluminal flow perturbations while it minimizes the confounding issue of concomitant (and often less well characterized) ch...

Atherosclerosis and calcium signalling in endothelial cells

“…Moreover, it is now established that IH does not occur randomly throughout the circulatory system, but occurs much more frequently near arterial bifurcations and in areas of high vessel curvature (Gimbrone, 1999). IH is strongly associated with disturbed haemodynamic characteristics, such as flow detachment from the arterial wall, flow recirculation and oscillatory flow.…”

“…In linear sections of the vasculature with steady laminar flow and relatively high wall shear stress (greater than 1 Pa), EC are well aligned in the direction of flow and cell-cell junctions are tight (Gimbrone, 1999). As a consequence, the endothelium is a highly stable cell population, with a very low rates of proliferation and death (Davies, 2000), and low permeability to blood-borne macromolecules, such as LDLs (Schachter, 1997).…”

Beneficial effects of pomegranate juice on oxidation-sensitive genes and endothelial nitric oxide synthase activity at sites of perturbed shear stress

“…Perturbed shear stress alone or high shear stress associated with other classical risk factors of atherosclerosis may trigger signal transduction events that in turn may lead to endothelial dysfunction and enhanced atherogenesis (2)(3)(4). It has been demonstrated that areas highly prone to atherosclerosis have unique patterns of disturbed flow, characterized by regions of flow separation, recirculation, and temporal and spatial gradients of shear stress (4).…”

“…NO controls vascular oxidative stress and the expression of redox-regulated genes (13,14). Evidence exists that eNOS activity is reduced at sites of perturbed shear stress (2,(5)(6)(7)(8)11).…”

Transient Mechanoactivation of Neutral Sphingomyelinase in Caveolae to Generate Ceramide

“…After 15 min to 1 h, FAK and c-Jun N-terminal kinase (JNK) are activated, at least in culture systems (12). Later, transcription factors will be activated to alter gene expression (2,13,14) and, with time, to modulate endothelial cell phenotype, cell adhesion, and even atherogenesis (2,14). The mechanisms mediating these effects, especially the key initiating mechanosensing molecule, remain largely unknown.…”