Monocyte accumulation in mouse atherogenesis is progressive and proportional to extent of disease
Open accessAbstract
Monocytes participate importantly in the pathogenesis of atherosclerosis, but their spatial and temporal recruitment from circulation remains uncertain. This study tests the hypothesis that monocyte accumulation in atheroma correlates with the extent of disease by using a sensitive and simple quantitative assay that allows tracking of highly enriched populations of blood monocytes. A two-step isolation method yielded viable and functionally intact highly enriched peripheral blood monocyte populations (>90%). Recipient mice received syngeneic monocytes labeled in two ways: by transgenically expressing EGFP or with a radioactive tracer [ 111 In]oxine. After 5 days, more labeled cells accumulated in the aorta, principally the aortic root and ascending aorta, of 10-wk-old ApoE −/− compared with 10-wk-old C57BL/6 mice (223 ± 3 vs. 87 ± 22 cells per aorta). Considerably more monocytes accumulated in 20-wk-old ApoE −/− mice on either chow (314 ± 41 cells) or high-cholesterol diet (395 ± 53 cells). Fifty-week-old ApoE −/− mice accumulated even more monocytes in the aortic root, ascending aorta, and thoracic aorta after both chow (503 ± 67 cells) or high-cholesterol diet (648 ± 81 cells). Labeled monocyte content in the aorta consistently correlated with lesion surface area. These data indicate that monocytes accumulate continuously during atheroma formation, accumulation increases in proportion to lesion size, and recruitment is augmented with hypercholesterolemia. These results provide insights into mechanisms of atherogenesis and have implications for the duration of therapies directed at leukocyte recruitment.
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Lesional macrophages mainly come from circulating monocytes that enter atherosclerosis-prone arterial wall sites and growing plaques.
“Macrophages in atherosclerotic lesions mainly originate from circulating monocytes, which migrate into atherosclerosis-susceptible sites of the arterial wall and into the growing atherosclerotic lesions139,140.”
From Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities (2019) · cites this paper as [139]
Cites
Inflammation in atherosclerosis
Libby, P. (2002) · Nature · doi:10.1038/nature01323 · Cited by 8,315 · see citing works
Self-citationInflammation in Atherosclerosis
Libby, P. (2012) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.108.179705 · Cited by 3,748 · see citing works
Self-citationSpontaneous Hypercholesterolemia and Arterial Lesions in Mice Lacking Apolipoprotein E
Zhang, S. H., Reddick, R. L., Piedrahita, J. A., & Maeda, N. (1992) · Science · doi:10.1126/science.1411543 · Cited by 2,237 · see citing works
Boring, L., Gosling, J., Cleary, M., & Charo, I. F. (1998) · Nature · doi:10.1038/29788 · Cited by 1,965 · see citing works
Borst, O., Walker, B., Münzer, P., Russo, A., Schmid, E., Faggio, C., Bigalke, B., Laufer, S., Gawaz, M., & Lang, F. J. W. (2013) · Cellular Physiology and Biochemistry · doi:10.1159/000350110 · Cited by 1,867 · see citing works
Platelets in inflammation and atherogenesis
Gawaz, M. (2005) · Journal of Clinical Investigation · doi:10.1172/jci27196 · Cited by 1,471 · see citing works
Subpopulations of Mouse Blood Monocytes Differ in Maturation Stage and Inflammatory Response
Sunderkötter, C., Nikolic, T., Dillon, M. J., van Rooijen, N., Stehling, M., Drevets, D. A., & Leenen, P. J. M. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.172.7.4410 · Cited by 1,124 · see citing works
Frostegård, J., Ulfgren, A., Nyberg, P., Hedin, U., Swedenborg, J., Andersson, U., & Hansson, G. K. (1999) · Atherosclerosis · doi:10.1016/s0021-9150(99)00011-8 · Cited by 1,002 · see citing works
Nakashima, Y., Raines, E. W., Plump, A. S., Breslow, J. L., & Ross, R. (1998) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.18.5.842 · Cited by 917 · see citing works
Reduction of atherosclerosis in mice by inhibition of CD40 signalling
Mach, F., Schönbeck, U., Sukhova, G. K., Atkinson, E., & Libby, P. (1998) · Nature · doi:10.1038/28204 · Cited by 910 · see citing works
Self-citationInnate and acquired immunity in atherogenesis
Binder, C. J., Chang, M.-K., Shaw, P. X., Miller, Y. I., Hartvigsen, K., Dewan, A. K., & Witztum, J. L. (2002) · Nature Medicine · doi:10.1038/nm1102-1218 · Cited by 642 · see citing works
Dynamic Imaging of Allogeneic Mesenchymal Stem Cells Trafficking to Myocardial Infarction
Kraitchman, D. L., Tatsumi, M., Gilson, W. D., Ishimori, T., Kedziorek, D., Walczak, P., Segars, W. P., Chen, H. H., Fritzges, D., Izbudak, I., et al. (2005) · Circulation · doi:10.1161/circulationaha.105.537480 · Cited by 602 · see citing works
Hajra, L., Evans, A. I., Chen, M., Hyduk, S. J., Collins, T., & Cybulsky, M. I. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.16.9052 · Cited by 569 · see citing works
Llodrá, J., Angeli, V., Liu, J. J., Trogan, E., Fisher, E. A. A., & Randolph, G. J. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0403259101 · Cited by 509 · see citing works
Deficiency of cathepsin S reduces atherosclerosis in LDL receptor–deficient mice
Sukhova, G. K., Zhang, Y., Pan, J.-H., Wada, Y., Yamamoto, T., Naito, M., Kodama, T., Tsimikas, S., Witztum, J. L., Lu, M. L., et al. (2003) · Journal of Clinical Investigation · doi:10.1172/jci14915 · Cited by 374 · see citing works
Self-citationDansky, H. M., Charlton, S. A., Harper, M. M., & Smith, J. D. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.9.4642 · Cited by 349 · see citing works
Flow cytometric identification of murine neutrophils and monocytes
Lagasse, E., & Weissman, I. L. (1996) · Journal of Immunological Methods · doi:10.1016/0022-1759(96)00138-x · Cited by 341 · see citing works
Deficiency of cathepsin S reduces atherosclerosis in LDL receptor–deficient mice
Sukhova, G. K., Zhang, Y., Pan, J., et al. (2003) · Journal of Clinical Investigation · doi:10.1172/jci200314915 · Cited by 314 · see citing works
Laurat, E., Poirier, B., Tupin, E., Caligiuri, G., Hansson, G. K., Bariety, J., & Nicoletti, A. (2001) · Circulation · doi:10.1161/01.cir.104.2.197 · Cited by 288 · see citing works
Buono, C., Come, C. E., Stavrakis, G., Maguire, G. F., Connelly, P. W., & Lichtman, A. H. (2003) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000059419.11002.6e · Cited by 288 · see citing works
Platelets and Chemokines in Atherosclerosis
Weber, C. (2005) · Circulation Research · doi:10.1161/01.res.0000160077.17427.57 · Cited by 265 · see citing works
Lymphocytes are important in early atherosclerosis
Song, L., Leung, C. C., & Schindler, C. (2001) · Journal of Clinical Investigation · doi:10.1172/jci11380 · Cited by 247 · see citing works
Heterozygous osteopetrotic (op) mutation reduces atherosclerosis in LDL receptor- deficient mice.
Rajavashisth, T. B., Qiao, J. H., Tripathi, S., Tripathi, J., Mishra, N. K., Hua, M., Wang, X. P., Loussararian, A. H., Clinton, S. K., Libby, P., et al. (1998) · Journal of Clinical Investigation · doi:10.1172/jci119891 · Cited by 245 · see citing works
Self-citationEriksson, E. E., Xie, X., Werr, J., et al. (2001) · The Journal of Experimental Medicine · doi:10.1084/jem.194.2.205 · Cited by 219 · see citing works
Lymphocytes are important in early atherosclerosis
Song, L., Leung, C. C., & Schindler, C. (2001) · Journal of Clinical Investigation · doi:10.1172/jci200111380 · Cited by 201 · see citing works
Lymphocyte Populations in Atherosclerotic Lesions of ApoE −/− and LDL Receptor −/− Mice
Roselaar, S. E., Kakkanathu, P. X., & Daugherty, A. (1996) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.16.8.1013 · Cited by 191 · see citing works
Patel, S. S., Thiagarajan, R., Willerson, J. T., & Yeh, E. T. H. (1998) · Circulation · doi:10.1161/01.cir.97.1.75 · Cited by 182 · see citing works
Lessner, S. M., Prado, H. L., Waller, E. K., & Galis, Z. S. (2002) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)61163-7 · Cited by 166 · see citing works
Drevets, D. A., Dillon, M. J., Schawang, J. S., van Rooijen, N., Ehrchen, J. M., Sunderkötter, C. H., & Leenen, P. J. M. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.172.7.4418 · Cited by 160 · see citing works
Buono, C., Pang, H. B., Uchida, Y., Libby, P., Sharpe, A. H., & Lichtman, A. H. (2004) · Circulation · doi:10.1161/01.cir.0000127121.16815.f1 · Cited by 155 · see citing works
Self-citationEriksson, E. E., Xie, X., Werr, J., Thorén, P., & Lindbom, L. (2001) · The FASEB Journal · doi:10.1096/fj.00-0537com · Cited by 143 · see citing works
New Mechanisms and Pathways for Monocyte Recruitment
Müller, W. A. (2001) · The Journal of Experimental Medicine · doi:10.1084/jem.194.9.f47 · Cited by 126 · see citing works
Groot, P. H. E., van Vlijmen, B. J. M., Benson, G. M., Hofker, M. H., Schiffelers, R. M., Vidgeon-Hart, M., & Havekes, L. M. (1996) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.16.8.926 · Cited by 113 · see citing works
Goldschmidt‐Clermont, P. J., Creager, M. A., Lorsordo, D. W., Lam, G. K. W., Wassef, M. K., & Dzau, V. J. (2005) · Circulation · doi:10.1161/circulationaha.105.577460 · Cited by 97 · see citing works
Reckless, J., Rubin, E. M., Verstuyft, J. B., Metcalfe, J. C., & Grainger, D. J. (1999) · Circulation · doi:10.1161/01.cir.99.17.2310 · Cited by 64 · see citing works
Kim, C. J., Khoo, J. C., Gillotte-Taylor, K., et al. (2000) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.20.8.1976 · Cited by 47 · see citing works
Steinberg, D. H., Khoo, J. C., Glass, C. K., et al. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.8.4040 · Cited by 27 · see citing works
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Nahrendorf, M., Swirski, F. K., Aikawa, E., Stangenberg, L., Wurdinger, T., Figueiredo, J.-L., Libby, P., Weissleder, R., & Pittet, M. J. (2007) · The Journal of Experimental Medicine · doi:10.1084/jem.20070885 · Cited by 2,300 · see citing works
Self-citationInflammation in Atherosclerosis
Libby, P., Ridker, P. M., & Hansson, G. K. (2009) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2009.09.009 · Cited by 2,228 · see citing works
Self-citationMonocytes and macrophages: developmental pathways and tissue homeostasis
Ginhoux, F., & Jung, S. (2014) · Nature Reviews Immunology · doi:10.1038/nri3671 · Cited by 1,840 · see citing works
Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities
Bäck, M., Yurdagul, A., Tabas, I., Öörni, K., & Kovanen, P. T. (2019) · Nature Reviews Cardiology · doi:10.1038/s41569-019-0169-2 · Cited by 1,341 · see citing works
Macrophage death and defective inflammation resolution in atherosclerosis
Tabas, I. (2010) · Nature Reviews Immunology · doi:10.1038/nri2675 · Cited by 1,120 · see citing works
Local proliferation dominates lesional macrophage accumulation in atherosclerosis
Robbins, C. S., Hilgendorf, I., Weber, G. F., Theurl, I., Iwamoto, Y., Figueiredo, J.-L., Gorbatov, R., Sukhova, G. K., Gerhardt, L. M. S., Smyth, D., et al. (2013) · Nature Medicine · doi:10.1038/nm.3258 · Cited by 1,041 · see citing works
Self-citationMonocytes in atherosclerosis: subsets and functions
Woollard, K. J., & Geissmann, F. (2010) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2009.228 · Cited by 890 · see citing works
Inflammation in Atherosclerosis: Transition From Theory to Practice
Libby, P., Okamoto, Y., Rocha, V. Z., & Folco, E. (2010) · Circulation Journal · doi:10.1253/circj.cj-09-0706 · Cited by 799 · see citing works
Self-citationMacrophages in health and disease
Park, M. D., Silvin, A., Ginhoux, F., & Merad, M. (2022) · Cell · doi:10.1016/j.cell.2022.10.007 · Cited by 644 · see citing works
Nanoparticle PET-CT Imaging of Macrophages in Inflammatory Atherosclerosis
Nahrendorf, M., Zhang, H., Hembrador, S., Panizzi, P., Sosnovik, D. E., Aikawa, E., Libby, P., Swirski, F. K., & Weissleder, R. (2008) · Circulation · doi:10.1161/circulationaha.107.741181 · Cited by 559 · see citing works
Self-citationKim, K., Shim, D., Lee, J. S., Zaitsev, K., Williams, J. W., Kim, K.-W., Jang, M.-Y., Seok Jang, H., Yun, T. J., Lee, S. H., et al. (2018) · Circulation Research · doi:10.1161/circresaha.118.312804 · Cited by 434 · see citing works
Cardilo‐Reis, L., Gruber, S., Schreier, S. M., Drechsler, M., Papac‐Milicevic, N., Weber, C., Wagner, O., Stangl, H., Soehnlein, O., & Binder, C. J. (2012) · EMBO Molecular Medicine · doi:10.1002/emmm.201201374 · Cited by 292 · see citing works
Hypoxia-inducible factors: key regulators of myeloid cells during inflammation
Lin, N., & Simon, M. C. (2016) · Journal of Clinical Investigation · doi:10.1172/jci84426 · Cited by 170 · see citing works
Increased ROS production and DNA damage in monocytes are biomarkers of aging and atherosclerosis
Jacinto, T. A., Meireles, G. S., Dias, A. T., Aires, R., Porto, M. L., Gava, A. L., Vasquez, E. C., Pereira, T. M. C., Campagnaro, B. P., & Meyrelles, S. S. (2018) · Biological Research · doi:10.1186/s40659-018-0182-7 · Cited by 86 · see citing works
Nagenborg, J., Goossens, P., Biessen, E. A. L., & Donners, M. M. P. C. (2017) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2017.10.005 · Cited by 50 · see citing works
Functional Genomics of the 9p21.3 Locus for Atherosclerosis: Clarity or Confusion?
Chen, H.-H., Almontashiri, N. A. M., Antoine, D., & Stewart, A. F. R. (2014) · Current Cardiology Reports · doi:10.1007/s11886-014-0502-7 · Cited by 45 · see citing works
Imaging macrophage development and fate in atherosclerosis and myocardial infarction
Swirski, F. K., & Nahrendorf, M. (2013) · Immunology & Cell Biology · doi:10.1038/icb.2012.72 · Cited by 23 · see citing works
Self-citation
- Authors
- Swirski, F. K., Pittet, M. J., Kircher, M. F., Aikawa, E., Jaffer, F. A., Libby, P., & Weissleder, R.
- Affiliations
- *Center for Molecular Imaging Research and Donald W. Reynolds Cardiovascular Clinical Research Center on Atherosclerosis at Harvard Medical School, Massachusetts General Hospital and Harvard Medical School, CNY 149, Charlestown, MA 02129; and
- Harvard University (US)
- Brigham and Women's Hospital (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2006-07-05
- Volume
- 103
- Issue
- 27
- Pages
- 10340-10345
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1502459
- OpenAlex
- W1992958840
- Cited by
- 367
- References
- 37
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 10 · 2023: 16 · 2022: 6 · 2021: 25 · 2020: 18 · 2019: 23 · 2018: 19 · 2017: 17 · 2016: 22 · 2015: 20 · 2014: 29 · 2013: 21 · 2012: 29
- FWCI
- 6.31
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- American Heart Association
- Massachusetts General Hospital
- National Heart, Lung, and Blood Institute (U01HL080731)
- National Cancer Institute (R24-CA-92782, R24CA092782)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cerebrovascular and Carotid Artery Diseases
- Keywords
- monocyte accumulation, atherogenesis, atherosclerosis, monocyte recruitment, ApoE-deficient mice, high-cholesterol diet, hypercholesterolemia, EGFP transgenic mice, indium-111 oxine, aortic root, leukocyte recruitment, disease progression
- MeSH terms
- Animals, Apolipoproteins E, Cell Movement, Cell Separation, Cholesterol, Monocytes, Signal Transduction, Mice, Knockout, Disease Progression, Atherosclerosis, Mice
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