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CD163+ macrophages promote angiogenesis and vascular permeability accompanied by inflammation in atherosclerosis.

ABSTRACT: Intake of hemoglobin by the hemoglobin-haptoglobin receptor CD163 leads to a distinct alternative non-foam cell antiinflammatory macrophage phenotype that was previously considered atheroprotective. Here, we reveal an unexpected but important pathogenic role for these macrophages in atherosclerosis. Using human atherosclerotic samples, cultured cells, and a mouse model of advanced atherosclerosis, we investigated the role of intraplaque hemorrhage on macrophage function with respect to angiogenesis, vascular permeability, inflammation, and plaque progression. In human atherosclerotic lesions, CD163+ macrophages were associated with plaque progression, microvascularity, and a high level of HIF1α and VEGF-A expression. We observed irregular vascular endothelial cadherin in intraplaque microvessels surrounded by CD163+ macrophages. Within these cells, activation of HIF1α via inhibition of prolyl hydroxylases promoted VEGF-mediated increases in intraplaque angiogenesis, vascular permeability, and inflammatory cell recruitment. CD163+ macrophages increased intraplaque endothelial VCAM expression and plaque inflammation. Subjects with homozygous minor alleles of the SNP rs7136716 had elevated microvessel density, increased expression of CD163 in ruptured coronary plaques, and a higher risk of myocardial infarction and coronary heart disease in population cohorts. Thus, our findings highlight a nonlipid-driven mechanism by which alternative macrophages promote plaque angiogenesis, leakiness, inflammation, and progression via the CD163/HIF1α/VEGF-A pathway.

SUBMITTER: Guo L

PROVIDER: S-EPMC5824873 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Neopterin, a metabolite of GTP, is produced by activated macrophages and is abundantly expressed within atherosclerotic lesions in human aorta and carotid and coronary arteries. We aimed to clarify the influence of neopterin on both vascular inflammation and atherosclerosis, as neither effect had been fully assessed. METHODS AND RESULTS:We investigated neopterin expression in coronary artery lesions and plasma from patients with coronary artery disease. We assessed the atheroprotective effects of neopterin in vitro using human aortic endothelial cells, human monocyte-derived macrophages, and human aortic smooth muscle cells. In vivo experiments included a study of aortic lesions in apolipoprotein E-deficient mice. Neopterin expression in coronary artery lesions and plasma was markedly increased in patients with versus without coronary artery disease. In human aortic endothelial cells, neopterin reduced proliferation and TNF-? (tumor necrosis factor ?)-induced upregulation of MCP-1 (monocyte chemotactic protein 1), ICAM-1 (intercellular adhesion molecule 1), and VCAM-1 (vascular cell adhesion molecule 1). Neopterin attenuated TNF-?-induced monocyte adhesion to human aortic endothelial cells and the inflammatory macrophage phenotype via NF-?B (nuclear factor-?B) downregulation. Neopterin suppressed oxidized low-density lipoprotein-induced foam cell formation associated with CD36 downregulation and upregulation of ATP-binding cassette transporters A1 and G1 in human monocyte-derived macrophages. In human aortic smooth muscle cells, neopterin suppressed angiotensin II-induced migration and proliferation via c-Src/Raf-1/ERK1/2 downregulation without inducing apoptosis. Exogenous neopterin administration and endogenous neopterin attenuation with its neutralizing antibody for 4 weeks retarded and promoted, respectively, the development of aortic atherosclerotic lesions in apolipoprotein E-deficient mice. CONCLUSIONS:Our results indicate that neopterin prevents both vascular inflammation and atherosclerosis and may be induced to counteract the progression of atherosclerotic lesions. Consequently, neopterin could be of use as a novel therapeutic target for atherosclerotic cardiovascular diseases.

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CD163+ macrophages promote angiogenesis and vascular permeability accompanied by inflammation in atherosclerosis.

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