Monocyte accumulation in mouse atherogenesis is progressive and proportional to extent of disease.
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.
Swirski
Filip K
FK
*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.|Cardiovascular Division, Department of Medicine and Donald W. Reynolds Cardiovascular Clinical Research Center on Atherosclerosis at Harvard Medical School, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115.
Pittet
Mikael J
MJ
*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.
Kircher
Moritz F
MF
*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.
Aikawa
Elena
E
*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.
Jaffer
Farouc A
FA
*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.
Libby
Peter
P
Cardiovascular Division, Department of Medicine and Donald W. Reynolds Cardiovascular Clinical Research Center on Atherosclerosis at Harvard Medical School, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115.
Weissleder
Ralph
R
*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 weissleder@helix.mgh.harvard.edu.
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement; D002469:Cell Separation; D002784:Cholesterol / Q000097:blood; D018450:Disease Progression; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology* / Q000378:metabolism; D015398:Signal Transduction
D001057:Apolipoproteins E; D002784:Cholesterol