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.
View: Text | PDF
Research Article Angiogenesis Vascular biology Article has an altmetric score of 11

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

×

Figure 3

Inhibition of PHDs by relative iron deprivation within M(Hb) macrophages increases HIF1α/VEGF-A signaling and promotes angiogenesis.

Options: View larger image (or click on image) Download as PowerPoint
Inhibition of PHDs by relative iron deprivation within M(Hb) macrophages...
(A) Intracellular free iron levels in control [M(con)] or HH-differentiated [M(Hb)] human macrophages (n = 4 per group). (B) PHD2 activity of human macrophages after HH treatment compared with control (n = 5 per group). (C and D) Immunoblotting of human macrophages (n = 4 per group) with quantitation of densitometry for HIF1α-OH and PHD2. (E) Immunoblotting of human macrophages (n = 4 per group) with quantitation of densitometry for HIF-1α. (lane 1: control macrophages; lane 2: HH-stimulated macrophages; lane 3: control macrophages + 700 nM hepcidin; lane 4: HH-stimulated macrophages + 7 00 nM hepcidin). (F) ELISA analysis of macrophage supernatants for VEGF-A (n = 5 per group). As in E, the bars represent, from left to right: control macrophages, HH-stimulated macrophages, control macrophages plus 700 nM hepcidin, and HH-stimulated macrophages plus 700 nM hepcidin. (G) Tube formation assays of HAECs with macrophage supernatant. Relative tube-forming abilities are shown with representative images on top and quantitated tube-formation index below (n = 5 per group). Scale bars: 200 μm. All error bars indicate the mean ± SEM. Comparisons between 2 groups were conducted using a 2-sided Student’s t test. For multiple group comparisons, a 1-way ANOVA was applied. If the variance ratio test (F test) was significant, a more detailed post-hoc analysis of differences between groups was made using a Tukey-Kramer honest significant difference test. *P < 0.05 versus control in A–D versus other groups in E–G.