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Cited by 1,016Atherosclerosis and Cardiovascular DiseasesCholesterol and Lipid MetabolismNitric Oxide and Endothelin Effects

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Recent insights into the cellular biology of atherosclerosis

Open access
Tabas, Ira, García-Cardeña, Guillermo, Owens, Gary K.·2015·Journal of Cell Biology
DOI 10.1083/jcb.201412052PMC PMC4395483
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Abstract

Atherosclerosis occurs in the subendothelial space (intima) of medium-sized arteries at regions of disturbed blood flow and is triggered by an interplay between endothelial dysfunction and subendothelial lipoprotein retention. Over time, this process stimulates a nonresolving inflammatory response that can cause intimal destruction, arterial thrombosis, and end-organ ischemia. Recent advances highlight important cell biological atherogenic processes, including mechanotransduction and inflammatory processes in endothelial cells, origins and contributions of lesional macrophages, and origins and phenotypic switching of lesional smooth muscle cells. These advances illustrate how in-depth mechanistic knowledge of the cellular pathobiology of atherosclerosis can lead to new ideas for therapy.

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Figure 1. Vascular endothelial cells and the development of early atherosclerotic lesions. Early lesions of atherosclerosis in the human carotid artery develop in the area of a major curvature (carotid sinus) exposed to low time-average shear stress, a high oscillatory shear index, and steep temporal and spatial gradients. Endothelial cells at this site display an atheroprone phenotype, which promotes a proinflammatory milieu driven by the priming of the NF-κB signaling pathway, which is then perpetuated in response to subendothelial apoB LPs. NF-κB activation promotes the entry of blood-borne monocytes (blue cells) through the junctions of endothelial cells (orange cells) into the intima, and there, monocytes differentiate into macrophages (red cells). In contrast, arterial geometries that are exposed to uniform laminar flow evoke an atheroprotective endothelial cell phenotype driven by the transcriptional integrators KLF2 and KLF4. This atheroprotective endothelial phenotype, together with a decrease in LP retention, promotes an antiinflammatory and antithrombotic environment that affords relative protection from atherosclerotic lesion development.
Figure 1. Vascular endothelial cells and the development of early atherosclerotic lesions. Early lesions of atherosclerosis in the human carotid artery develop in the area of a major curvature (carotid sinus) exposed to low time-average shear stress, a high oscillatory shear index, and steep temporal and spatial gradients. Endothelial cells at this site display an atheroprone phenotype, which promotes a proinflammatory milieu driven by the priming of the NF-κB signaling pathway, which is then perpetuated in response to subendothelial apoB LPs. NF-κB activation promotes the entry of blood-borne monocytes (blue cells) through the junctions of endothelial cells (orange cells) into the intima, and there, monocytes differentiate into macrophages (red cells). In contrast, arterial geometries that are exposed to uniform laminar flow evoke an atheroprotective endothelial cell phenotype driven by the transcriptional integrators KLF2 and KLF4. This atheroprotective endothelial phenotype, together with a decrease in LP retention, promotes an antiinflammatory and antithrombotic environment that affords relative protection from atherosclerotic lesion development.CC BY-NC-SA · PubMed Central
Figure 2. Proatherogenic roles of lesional macrophages. (1) The two-way interplay between activated, dysfunctional endothelium, i.e., as a result of flow disturbances, and apoB LP retention triggers the entry of inflammatory monocytes into the subendothelial intima (red arrows depict endothelial dysfunction triggered by retained LPs in the intima). (2) The macrophages (MΦ) ingest the retained LPs through various pathways and become lipid-loaded foam cells. (3) Lesional macrophages can proliferate, particularly in advanced lesions. (4) Macrophages promote plaque progression by propagating a maladaptive, nonresolving inflammatory response characterized by an imbalance of inflammatory-to-proresolving mediators. Moreover, matrix metalloproteinases (MMPs) secreted by inflammatory macrophages can lead to thinning of the fibrous cap and plaque rupture. (5) Environmental factors in advanced lesions promote macrophage apoptosis, e.g., as a result of prolonged ER stress and/or oxidative stress. Apoptotic cell death may not be problematic if cleared efficiently by lesional phagocytes (efferocytosis). (6) However, in advanced atherosclerosis, this process goes awry, leading to postapoptotic necrosis. Necrotic cells, which can also develop through RIP3 activation (primary necrosis), release DAMPs, which amplify inflammation. These cells can also coalesce into areas, called necrotic cores, that promote plaque breakdown and thrombosis. ROS, reactive oxygen species.
Figure 2. Proatherogenic roles of lesional macrophages. (1) The two-way interplay between activated, dysfunctional endothelium, i.e., as a result of flow disturbances, and apoB LP retention triggers the entry of inflammatory monocytes into the subendothelial intima (red arrows depict endothelial dysfunction triggered by retained LPs in the intima). (2) The macrophages (MΦ) ingest the retained LPs through various pathways and become lipid-loaded foam cells. (3) Lesional macrophages can proliferate, particularly in advanced lesions. (4) Macrophages promote plaque progression by propagating a maladaptive, nonresolving inflammatory response characterized by an imbalance of inflammatory-to-proresolving mediators. Moreover, matrix metalloproteinases (MMPs) secreted by inflammatory macrophages can lead to thinning of the fibrous cap and plaque rupture. (5) Environmental factors in advanced lesions promote macrophage apoptosis, e.g., as a result of prolonged ER stress and/or oxidative stress. Apoptotic cell death may not be problematic if cleared efficiently by lesional phagocytes (efferocytosis). (6) However, in advanced atherosclerosis, this process goes awry, leading to postapoptotic necrosis. Necrotic cells, which can also develop through RIP3 activation (primary necrosis), release DAMPs, which amplify inflammation. These cells can also coalesce into areas, called necrotic cores, that promote plaque breakdown and thrombosis. ROS, reactive oxygen species.CC BY-NC-SA · PubMed Central
Figure 3. Ambiguity regarding the identity and origins of SMC, macrophages, and putative derivatives of these cells within advanced human atherosclerotic lesions. Lesional cells display remarkable heterogeneity as a result of effects of microenvironmental factors, including cytokines, inflammatory lipids, growth factors, dead cell debris, oxygen tension variations, and oxidative stress. For purposes of this figure, we have only considered data in intact human tissue specimens rather than studies in cultured cells or animal models. The solid arrows illustrate known pathways that give rise to lesion cells, whereas the dotted arrows indicate putative pathways not yet directly validated in humans. For example, cross-gender bone marrow transplant Y-chromosome lineage tracing studies provide clear evidence that myeloid cells, presumably monocytes, give rise to CD68+ macrophages but also Acta2+ SMC-like cells within advanced human coronary artery lesions. In contrast, there is no direct evidence that SMCs are the primary source of fibrous cap cells that produce extracellular matrix that stabilizes lesions because Acta2+ cells may be derived from SMCs, macrophages, or other cell types. Similarly, there is evidence that approximately half of the foam cells within advanced human coronary artery atherosclerotic lesions are Acta2+ and CD68+ (Allahverdian et al., 2014), but the origin of these cells is not clear.
Figure 3. Ambiguity regarding the identity and origins of SMC, macrophages, and putative derivatives of these cells within advanced human atherosclerotic lesions. Lesional cells display remarkable heterogeneity as a result of effects of microenvironmental factors, including cytokines, inflammatory lipids, growth factors, dead cell debris, oxygen tension variations, and oxidative stress. For purposes of this figure, we have only considered data in intact human tissue specimens rather than studies in cultured cells or animal models. The solid arrows illustrate known pathways that give rise to lesion cells, whereas the dotted arrows indicate putative pathways not yet directly validated in humans. For example, cross-gender bone marrow transplant Y-chromosome lineage tracing studies provide clear evidence that myeloid cells, presumably monocytes, give rise to CD68+ macrophages but also Acta2+ SMC-like cells within advanced human coronary artery lesions. In contrast, there is no direct evidence that SMCs are the primary source of fibrous cap cells that produce extracellular matrix that stabilizes lesions because Acta2+ cells may be derived from SMCs, macrophages, or other cell types. Similarly, there is evidence that approximately half of the foam cells within advanced human coronary artery atherosclerotic lesions are Acta2+ and CD68+ (Allahverdian et al., 2014), but the origin of these cells is not clear.CC BY-NC-SA · PubMed Central

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Metadata

Authors
Tabas, I., García-Cardeña, G., & Owens, G. K.
Affiliations
  • Columbia University Irving Medical Center (US)
  • Program in Human Biology and Translational Medicine, Harvard Medical School, Boston, MA 02115 4
  • University of Virginia (US)
Corresponding author
Tabas, Ira
ORCID
Venue
Journal of Cell Biology
Publisher
Rockefeller University Press
Published
2015-04-13
Volume
209
Issue
1
Pages
13-22
ISSN
  • 0021-9525 (ISSN-L)
  • 1540-8140
DOI
10.1083/jcb.201412052
PMC
PMC4395483
OpenAlex
W1949072443
Cited by
1,016
References
107
Citations by year
2026: 45 · 2025: 68 · 2024: 70 · 2023: 96 · 2022: 107 · 2021: 94 · 2020: 96 · 2019: 124 · 2018: 108 · 2017: 103 · 2016: 78 · 2015: 23
FWCI
9.82
Type
journal article
Language
en
Open access
Locations
  • The Journal of Cell Biology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
Funders
  • National Institutes of Health
  • National Institute on Aging (AG032443, R01AG032443)
  • National Heart, Lung, and Blood Institute (R44HL118826, HL057353, HL087867, HL107497, HL075662, HL121008, HL118826, R01HL087867, R01HL057353, R01HL075662, R37HL057353, R01HL121008, R01HL107497, R41HL118826)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
  • Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
Keywords
atherosclerosis, endothelial dysfunction, disturbed blood flow, nonresolving inflammation, arterial thrombosis, end-organ ischemia, mechanotransduction, endothelial inflammation, macrophage origin, smooth muscle cell phenotypic switching, atherosclerosis treatment
MeSH terms
Animals, Endothelium, Vascular, Humans, Macrophages, Muscle, Smooth, Vascular, Myocytes, Smooth Muscle, Mechanotransduction, Cellular, Endothelial Cells, Atherosclerosis

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