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Flow signaling and atherosclerosis

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Abstract

Atherosclerosis rarely develops in the region of arteries exposed to undisturbed flow (u-flow, unidirectional flow). Instead, atherogenesis occurs in the area exposed to disturbed flow (d-flow, multidirectional flow). Based on these general pathohistological observations, u-flow is considered to be athero-protective, while d-flow is atherogenic. The fact that u-flow and d-flow induce such clearly different biological responses in the wall of large arteries indicates that these two types of flow activate each distinct intracellular signaling cascade in vascular endothelial cells (ECs), which are directly exposed to blood flow. The ability of ECs to differentially respond to the two types of flow provides an opportunity to identify molecular events that lead to endothelial dysfunction and atherosclerosis. In this review, we will focus on various molecular events, which are differentially regulated by these two flow types. We will discuss how various kinases, ER stress, inflammasome, SUMOylation, and DNA methylation play roles in the differential flow response, endothelial dysfunction, and atherosclerosis. We will also discuss the interplay among the molecular events and how they coordinately regulate flow-dependent signaling and cellular responses. It is hoped that clear understanding of the way how the two flow types beget each unique phenotype in ECs will lead us to possible points of intervention against endothelial dysfunction and cardiovascular diseases.

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Fig. 1
Fig. 2

(Obtained permission to reproduce from Wolters Kluwer Health)

Fig. 3

Reprinted from Lerner-Marmarosh et al. [72], and obtained permission to reproduce from Wolters Kluwer Health

Fig. 4
Fig. 5

Reprinted and modified from Akaike et al. [77]

Fig. 6

Modified from Kayagaki et al. [114] with permission of the publisher. Copyright ©2015, Nature Publishing Group

Fig. 7

Modified from Woo et al. with permission of the publisher [227]

Fig. 8
Fig. 9

Reprinted from Heo, Berk, and Abe [36]

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Acknowledgements

The work was supported by Grants from the National Institute of Health to Dr. Abe (HL-130193, HL-123346, HL-118462), and from American Heart Association to Dr. Le (AHA 13SDG14500033).

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Authors and Affiliations

  1. Department of Cardiology, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Unit 1101, 1515 Holcombe Blvd., Houston, Texas, 77030-4009, USA

    Nhat-Tu Le, Uday G. Sandhu, Raymundo A. Quintana-Quezada, Nguyet Minh Hoang, Keigi Fujiwara & Jun-ichi Abe

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  1. Nhat-Tu Le
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  2. Uday G. Sandhu
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Le, NT., Sandhu, U.G., Quintana-Quezada, R.A. et al. Flow signaling and atherosclerosis. Cell. Mol. Life Sci. 74, 1835–1858 (2017). https://doi.org/10.1007/s00018-016-2442-4

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