Coronary endothelium expresses a pathologic gene pattern compared to aortic endothelium: Correlation of asynchronous hemodynamics and pathology in vivo

Dancu, Michael B.; Tarbell, John M.

doi:10.1016/j.atherosclerosis.2006.05.042

Cited by 34 publications

(30 citation statements)

References 29 publications

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“…Furthermore, nuclei are discrete objects and hence easy to recognize by simple automated techniques, whereas cell boundaries constitute a network of lines, each of which has to be attributed to 2 cells, a process that is complicated by the existence of breaks in stained boundaries. In earlier studies, 15,19,23 nuclei were stained with hematoxylin, but the use of fluorescent dyes gives greater and more even contrast, again facilitating the automated analysis that is essential to creating high resolution maps over large areas.…”

Section: Discussionmentioning

confidence: 99%

Morphological Evidence for a Change in the Pattern of Aortic Wall Shear Stress With Age

Bond

Iftikhar

Bharath

et al. 2011

ATVB

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Objective-The distribution of atherosclerosis around branch sites changes with age in human and rabbit aortas. We tested whether that reflects a change in the pattern of wall shear stress by examining shear-dependent morphological features of endothelial cells. Methods and Results-Endothelial cells and their nuclei align and elongate with applied shear. These parameters were examined in the descending thoracic aorta of immature and mature rabbits. The use of Häutchen preparations, fluorescent stains, and automated image analysis allowed nuclear morphology to be mapped reliably at high resolution over large areas. Cells and their nuclei were most elongated downstream of branch ostia in immature aortas but upstream of them in mature aortas. Elongation was generally greater in mature animals, and nuclei aligned toward the ostia more in these animals, consistent with a greater flow into the branch. Morphology away from branches was indicative of helical flow in the aorta, with greatest shear on the dorsal wall, at both ages. Key Words: atherosclerosis Ⅲ blood flow Ⅲ endothelium Ⅲ shear stress T he prevalence of atherosclerosis varies greatly from one region of the arterial system to another. This patchy distribution is particularly striking near branch points and in curved vessels, consistent with the development of disease depending on mechanical factors. The current consensus is that lesions occur most frequently where blood flow exerts a low, oscillatory shear stress on the wall. 1,2 We have drawn attention to age-related changes in the pattern of lesions around branch ostia in the human aorta, 3 and we have demonstrated similar changes in the pattern of spontaneous 4 and diet-induced 5-7 lesions in rabbits. These changes could reflect alteration of the mechanical stresses acting on the wall or alteration of the relationship between mechanical stress and lesion development; the latter would imply that the low shear stress hypothesis cannot be valid at all ages. Conclusion-TheBlood flow velocity near the wall cannot be measured in vivo with sufficient spatial resolution to determine whether the pattern of wall shear stress around branch points changes with age. However, local wall shear stress can be inferred from endothelial morphology. In vitro studies have shown that endothelial cells and their nuclei align with the predominant flow direction and elongate with increasing shear stress. 8 -11 This relationship also seems to hold in vivo: patterns of cell morphology seen near branches correlate with the flow visualized in models of the branches, 12-14 and if flow or the orientation of the endothelium is altered, cells and their nuclei adjust their shape and alignment accordingly. [15][16][17][18] In a preliminary study using endothelial morphology to determine whether the pattern of shear stress near branches changes with age, 19 we measured nuclear orientation and elongation around the origins of intercostal arteries in aortas from immature and mature rabbits. Changes with age in the pattern of nuclear elongatio...

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Section: Discussionmentioning

confidence: 99%

Morphological Evidence for a Change in the Pattern of Aortic Wall Shear Stress With Age

Bond

Iftikhar

Bharath

et al. 2011

ATVB

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“…Indeed, turbulence, defined as blood flow exceeding the critical Reynolds number, occurs almost nowhere in the normal human circulatory system. The coronary circulation is uniquely predisposed to atherosclerosis (804), probably because of high intraluminal pressure and complete flow cessation and possible reversal during systole, a likely cause of the greatly suppressed eNOS activity observed in coronary compared with aortic endothelial cells (377 (375). Endothelial cells exposed to disturbed flow (FIGURE 6A) develop a proinflammatory phenotype with increased production of ROS, higher cell turnover, increased cell-cell permeability, and excess apoptosis.…”

Section: Initiation Of Atherosclerosis: Arterial Flow Patterns Esmentioning

confidence: 99%

Molecular Biology of Atherosclerosis

Hopkins

2013

Physiological Reviews

390

344

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At least 468 individual genes have been manipulated by molecular methods to study their effects on the initiation, promotion, and progression of atherosclerosis. Most clinicians and many investigators, even in related disciplines, find many of these genes and the related pathways entirely foreign. Medical schools generally do not attempt to incorporate the relevant molecular biology into their curriculum. A number of key signaling pathways are highly relevant to atherogenesis and are presented to provide a context for the gene manipulations summarized herein. The pathways include the following: the insulin receptor (and other receptor tyrosine kinases); Ras and MAPK activation; TNF-␣ and related family members leading to activation of NF-B; effects of reactive oxygen species (ROS) on signaling; endothelial adaptations to flow including G protein-coupled receptor (GPCR) and integrin-related signaling; activation of endothelial and other cells by modified lipoproteins; purinergic signaling; control of leukocyte adhesion to endothelium, migration, and further activation; foam cell formation; and macrophage and vascular smooth muscle cell signaling related to proliferation, efferocytosis, and apoptosis. This review is intended primarily as an introduction to these key signaling pathways. They have become the focus of modern atherosclerosis research and will undoubtedly provide a rich resource for future innovation toward intervention and prevention of the number one cause of death in the modern world.

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“…2,5,6 The coronary artery is characterized by asynchronous hemodynamics, wherein the wall shear stress from blood flow is out of phase with the circumferential strain from blood pressure 105 and this may play a role in determining the heterogeneous eNOS expression in the coronary arterial tree. 106,107 Further support for the role of hemodynamics in eNOS protein expression comes from studies in miniature swine following prolonged aerobic exercise training. 108 Following weeks of training, eNOS protein content was increased by over 50% in coronary arteries and small and large arterioles, but unaltered in coronary conduit and intermediate arterioles, 108 suggesting that steady state adaptations to exercise hemodynamic stimuli include nonuniform changes in eNOS expression that lead to an NO-mediated improvement in coronary resistance artery endothelium-dependent dilation.…”

Section: Heterogeneity Of Enos Expression In the Coronary Vascular Bedmentioning

confidence: 99%

Nitric oxide and coronary vascular endothelium adaptations in hypertension

Levy

Chung²,

Kroetsch

et al. 2009

VHRM

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This review highlights a number of nitric oxide (NO)-related mechanisms that contribute to coronary vascular function and that are likely affected by hypertension and thus become important clinically as potential considerations in prevention, diagnosis, and treatment of coronary complications of hypertension. Coronary vascular resistance is elevated in hypertension in part due to impaired endothelium-dependent function of coronary arteries. Several lines of evidence suggest that other NO synthase isoforms and dilators other than NO may compensate for impairments in endothelial NO synthase (eNOS) to protect coronary artery function, and that NO-dependent function of coronary blood vessels depends on the position of the vessel in the vascular tree. Adaptations in NOS isoforms in the coronary circulation to hypertension are not well described so the compensatory relationship between these and eNOS in hypertensive vessels is not clear. It is important to understand potential functional consequences of these adaptations as they will impact the efficacy of treatments designed to control hypertension and coronary vascular disease. Polymorphisms of the eNOS gene result in significant associations with incidence of hypertension, although mechanistic details linking the polymorphisms with alterations in coronary vasomotor responses and adaptations to hypertension are not established. This understanding should be developed in order to better predict those individuals at the highest risk for coronary vascular complications of hypertension. Greater endothelium-dependent dilation observed in female coronary arteries is likely related to endothelial Ca 2+ control and eNOS expression and activity. In hypertension models, the coronary vasculature has not been studied extensively to establish mechanisms for sex differences in NO-dependent function. Genomic and nongenomic effects of estrogen on eNOS and direct and indirect antioxidant activities of estrogen are discussed as potential mechanisms of interest in coronary circulation that could have implications for sex-and estrogen status-dependent therapy for hypertension and coronary dysfunction. The current review identifies some important basic knowledge gaps and speculates on the potential clinical relevance of hypertension adaptations in factors regulating coronary NO function.

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Coronary endothelium expresses a pathologic gene pattern compared to aortic endothelium: Correlation of asynchronous hemodynamics and pathology in vivo

Cited by 34 publications

References 29 publications

Morphological Evidence for a Change in the Pattern of Aortic Wall Shear Stress With Age

Morphological Evidence for a Change in the Pattern of Aortic Wall Shear Stress With Age

Molecular Biology of Atherosclerosis

Nitric oxide and coronary vascular endothelium adaptations in hypertension

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