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 7

CD163+ macrophages are associated with increased angiogenesis and microvessel permeability in human coronary artery plaques.

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CD163+ macrophages are associated with increased angiogenesis and microv...
(A–D) Human coronary artery microvessel permeability was assessed by EBD perfusion. (A) Representative images of EBD-perfused human coronary arteries, H&E-stained images, and confocal immunofluorescence images of CD163 (red) and VE-cadherin (yellow) or VE-cadherin (red) and VCAM (green) in an EBD-negative area (top row), EBD-positive area 1 (middle row), and EBD-positive area 2 (bottom row). Positive areas 1 and 2 are shown in progressively higher-magnification H&E-stained images from left to right in the second and third rows. Red and white arrowheads point to microvessels. Confocal images of the EBD-negative areas for CD163/VE-cadherin and VE-cadherin/VCAM are shown in the top row of columns 3 and 4, respectively, while the positive area 1 is shown for CD163/VE-cadherin in the middle rows of columns 3 and 4 (higher-magnification image on the right), and positive area 2 is shown for VE-cadherin/VCAM in the bottom of row of columns 3 and 4 (higher-magnification image on the right). (B–D) Quantification of microvessel density, CD163+ macrophages, and VCAM in an EBD-positive area versus an EBD-negative area (n = 6–8 per group). (E) The SNP rs7136716 was associated with human coronary artery atherosclerotic plaque rupture and risk of coronary artery disease. See Table 2 for SNP analysis of the CVPath cohort. Representative images show ruptured plaques in human coronary arteries from subjects with the rs7136717 AA genotype versus the those with the GG genotype. Scale bars: 500 μm. Arrowheads point to microvessels. (F) Microvessel density per plaque area at the ruptured coronary artery plaque site from individuals with 0 copies (AA genotype, n = 22) versus 2 copies of the minor allele (GG genotype, n = 25) who died of plaque rupture. (G) Relative CD163 mRNA expression in ruptured coronary artery plaques from AA versus GG genotype groups as measured by qPCR (n = 13 per group). (H) Cox proportional hazards ratio assessment for the association of the genetic variant rs7136717 with incident MI and incident CHD in the ARIC cohort (n = 3,225). Data represent the mean ± SD (B–D, F, and G) or ORs and 95% CI (H). P < 0.01 and P < 0.05, by 2-sided Student’s t test (B–D, F, and G). In the ARIC cohort, Cox proportional hazards models were used to examine the association of the genetic variant with incident MI and incident CHD, and the analyses were adjusted for age, sex, ancestry-informative principal components, and study center (H).