CD163+ macrophages promote angiogenesis and vascular permeability accompanied by inflammation in atherosclerosis
JournalJournal of Clinical Investigation
PublisherAmerican Society for Clinical Investigation
MetadataShow full item record
AbstractIntake 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 HIF1? and VEGF-A expression. We observed irregular vascular endothelial cadherin in intraplaque microvessels surrounded by CD163+ macrophages. Within these cells, activation of HIF1? 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/HIF1?/VEGF-A pathway. Copyright 2018 Blackwell Publishing Ltd. All rights reserved.
SponsorsThis study is supported by the CVPath Institute; the Woodruff Sciences Health Center at Emory University; and the Car- lyle Fraser Heart Center at Emory Hospital Midtown. CUC is supported by a grant from the CardioVascular Research Foundation (CVRF) of Korea. Genotyping of the CVPath cohort was supported by the National Heart, Lung, and Blood Institute (NHLBI) (HL111089, to NS). The ARIC study was funded in whole or in part with federal funds from the NHLBI, NIH, Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700003I, HHSN268201700005I, HHSN268201700004I, and HHSN2682017000021).
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85042749174&doi=10.1172%2fJCI93025&partnerID=40&md5=b775b8eda2fb03b8047d7ec561e761bc; http://hdl.handle.net/10713/9778