GM-CSF regulates intimal cell proliferation in nascent atherosclerotic lesions.
The contribution of intimal cell proliferation to the formation of early atherosclerotic lesions is poorly understood. We combined 5-bromo-2'-deoxyuridine pulse labeling with sensitive en face immunoconfocal microscopy analysis, and quantified intimal cell proliferation and Ly-6C(high) monocyte recruitment in low density lipoprotein receptor-null mice. Cell proliferation begins in nascent lesions preferentially at their periphery, and proliferating cells accumulate in lesions over time. Although intimal cell proliferation increases in parallel to monocyte recruitment as lesions grow, proliferation continues when monocyte recruitment is inhibited. The majority of proliferating intimal cells are dendritic cells expressing CD11c and major histocompatibility complex class II and 33D1, but not CD11b. Systemic injection of granulocyte/macrophage colony-stimulating factor (GM-CSF) markedly increased cell proliferation in early lesions, whereas function-blocking anti-GM-CSF antibody inhibited proliferation. These findings establish GM-CSF as a key regulator of intimal cell proliferation in lesions, and demonstrate that both proliferation and monocyte recruitment contribute to the inception of atherosclerosis.
Zhu
Su-Ning
SN
Toronto General Research Institute, University Health Network, Toronto, Ontario M5G 2C4, Canada.
Chen
Mian
M
Jongstra-Bilen
Jenny
J
Cybulsky
Myron I
MI
D000818:Animals; D000950:Antigens, Ly / Q000032:analysis; D050197:Atherosclerosis / Q000209:etiology*; D001973:Bromodeoxyuridine / Q000378:metabolism; D039521:CD11c Antigen / Q000032:analysis; D002465:Cell Movement; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000502:physiology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000502:physiology; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000032:analysis; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000502:physiology; D017539:Tunica Intima / Q000473:pathology*
D000950:Antigens, Ly; D039521:CD11c Antigen; C494192:Ly-6C antigen, mouse; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor; D001973:Bromodeoxyuridine