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The Role of Blood Flow in Determining the Sites of Atherosclerotic Plaques


The Role of Blood Flow in Determining the Sites of Atherosclerotic Plaques

Christina M Warboys et al. F1000 Med Rep.


Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipids and inflammatory cells along the inner walls of arteries, and is an underlying cause of cardiovascular disease. Atherosclerotic lesions develop predominantly at branches, bends, and bifurcations in the arterial tree because these sites are exposed to low or disturbed blood flow, which exerts low/oscillatory shear stress on the vessel wall. This mechanical environment alters endothelial cell physiology by enhancing inflammatory activation. In contrast, regions of the arterial tree that are exposed to uniform, unidirectional blood flow and experience high shear stress are protected from inflammation and lesion development. Shear stress is sensed by the endothelium via mechanoreceptors and is subsequently transduced into biochemical signals resulting in modulation of proinflammatory signaling pathways. In this article, we address the molecular mechanisms behind the spatial localization of vascular inflammation and atherosclerosis, with particular focus on studies by our own group of two key proinflammatory signaling pathways, the mitogen-activated protein kinase pathway and the nuclear factor-kappa-B pathway.


Figure 1.
Figure 1.. Leukocyte adhesion and transmigration
Proinflammatory signaling results in the increased expression of adhesion molecules such as E-selectin on endothelial cells, which facilitates “capture” of the leukocytes to the vessel wall. Chemokines secreted by endothelial cells activate leukocyte integrins, a process that promotes firm adhesion between leukocytes and endothelial cells via integrin-adhesion molecule interactions. Adherent leukocytes subsequently transmigrate through the endothelium to the underlying tissue. E-selectin, endothelial selectin; ICAM-1, intercellular adhesion molecule-1; IL-8, interleukin 8; MCP-1, monocyte chemotactic protein-1; VCAM-1, vascular cell adhesion molecule-1.
Figure 2.
Figure 2.. Atherosclerotic plaques occur at sites of low/disturbed blood flow
Atherosclerotic lesions form predominantly at regions of the arterial tree exposed to low/disturbed blood flow such as branches, bends, and bifurcations, whilst regions exposed to unidirectional high flow are spared. Two theories have been proposed that account for this localization: (1) the mass transport theory, where atherogenic material such as low-density lipoprotein (LDL) and leukocytes have better access to the arterial wall in areas of low flow or stagnation; and (2) the shear stress theory, where shear stress (mechanical drag) is sensed by endothelial cells, resulting in an altered phenotype. Low/oscillatory shear stress primes endothelial cells for inflammation by inducing adhesion molecule expression.
Figure 3.
Figure 3.. Inflammatory signaling pathways that are regulated by high shear stress
Both the mitogen-activated protein kinase (MAPK) and nuclear factor-kappa-B (NF-κB) signaling pathways are active at sites of the arterial tree exposed to low/oscillatory shear stress and are stimulated by proinflammatory cytokines leading to inflammation and lesion development. At sites of high shear stress, these signaling pathways are inhibited at several levels with a consequent inhibition of inflammation. AP-1, activating protein-1; ASK-1, apoptosis signal-regulating kinase 1; ICAM-1, intercellular adhesion molecule-1; IκB, inhibitory κB; IKK, IκB kinase; JNK, c-Jun N-terminal kinase; KLF-2, Krüppel-like factor-2; MKP-1, MAPK phosphatase-1; MKK, MAPK kinase; Nrf2, nuclear factor erythroid 2-related factor; Ox-LDL, oxidized low-density lipoprotein; P, phosphorylation; PKCζ, protein kinase C epsilon; TAK-1, transforming growth factor (TGF)-β activated kinase 1; VCAM-1, vascular cell adhesion molecule-1; Uq, ubiquitin.

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