CD163+ macrophages promote angiogenesis and vascular permeability accompanied by inflammation in atherosclerosis
Liang Guo, … , Renu Virmani, Aloke V. Finn
Liang Guo, … , Renu Virmani, Aloke V. Finn
Published February 19, 2018
Citation Information: J Clin Invest. 2018;128(3):1106-1124. https://doi.org/10.1172/JCI93025.
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Research Article Angiogenesis Vascular biology

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.

Authors

Liang Guo, Hirokuni Akahori, Emanuel Harari, Samantha L. Smith, Rohini Polavarapu, Vinit Karmali, Fumiyuki Otsuka, Rachel L. Gannon, Ryan E. Braumann, Megan H. Dickinson, Anuj Gupta, Audrey L. Jenkins, Michael J. Lipinski, Johoon Kim, Peter Chhour, Paul S. de Vries, Hiroyuki Jinnouchi, Robert Kutys, Hiroyoshi Mori, Matthew D. Kutyna, Sho Torii, Atsushi Sakamoto, Cheol Ung Choi, Qi Cheng, Megan L. Grove, Mariem A. Sawan, Yin Zhang, Yihai Cao, Frank D. Kolodgie, David P. Cormode, Dan E. Arking, Eric Boerwinkle, Alanna C. Morrison, Jeanette Erdmann, Nona Sotoodehnia, Renu Virmani, Aloke V. Finn

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Figure 8

Summary of the role of M(Hb) macrophages in plaque angiogenesis, permeability, vascular inflammation, and plaque progression.

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Summary of the role of M(Hb) macrophages in plaque angiogenesis, permeab...
In areas of IPH, HH complex ingestion by macrophages induces angiogenesis via activation of HIF1α, which is a consequence of intracellular Fe2+ deprivation and PHD2 inhibition. VEGF-A, which is secreted by macrophages via HIF1α activation, promotes angiogenesis, endothelial expression of VCAM, inflammatory cell recruitment, and vascular permeability via VEGF-A/VEGFR2 signaling. This may cause further IPH, RBC lysis, and more Hb ingestion by CD163+ macrophages. This vicious cycle causes plaque progression, which eventually leads to plaque rupture.