Citation: Journal of Clinical Investigation. 2018 Feb 19.Journal: The Journal of clinical investigation.Published: 2018ISSN: 0021-9738.Full author list: Guo L; Akahori H; Harari E; Smith SL; Polavarapu R; Karmali V; Otsuka F; Gannon RL; Braumann RE; Dickinson MH; Gupta A; Jenkins AL; Lipinski MJ; Kim J; Chhour P; de Vries PS; Jinnouchi H; Kutys R; Mori H; Kutyna MD; Torii S; Sakamoto A; Choi CU; Cheng Q; Grove ML; Sawan MA; Zhang Y; Cao Y; Kolodgie FD; Cormode DP; Arking DE; Boerwinkle E; Morrison AC; Erdmann J; Sotoodehnia N; Virmani R; Finn AV.UI/PMID: 29457790.Subject(s): IN PROCESS -- NOT YET INDEXEDInstitution(s): MedStar Health Research Institute | MedStar Heart & Vascular InstituteActivity type: Journal Article.Medline article type(s): Journal ArticleOnline resources: Click here to access onlineDigital Object Identifier: https://dx.doi.org/10.1172/JCI93025 (Click here)Abbreviated citation: J Clin Invest. 2018 Feb 19.Local Holdings: Available online from MWHC library: 1924 - present, Available in print through MWHC library: 1999 - March 2001.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 HIF1alpha and VEGF-A expression. We observed irregular vascular endothelial cadherin in intraplaque microvessels surrounded by CD163+ macrophages. Within these cells, activation of HIF1alpha 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/HIF1alpha/VEGF-A pathway.