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CD163+ macrophages promote angiogenesis and vascular permeability accompanied by inflammation in atherosclerosis
The Journal of Clinical Investigation ( IF 15.9 ) Pub Date : 2018-02-19 , DOI: 10.1172/jci93025
Liang Guo 1 , Hirokuni Akahori 2 , Emanuel Harari 1 , Samantha L Smith 1 , Rohini Polavarapu 2 , Vinit Karmali 2 , Fumiyuki Otsuka 1 , Rachel L Gannon 1 , Ryan E Braumann 1 , Megan H Dickinson 1 , Anuj Gupta 3 , Audrey L Jenkins 4 , Michael J Lipinski 4 , Johoon Kim 5 , Peter Chhour 5 , Paul S de Vries 6 , Hiroyuki Jinnouchi 1 , Robert Kutys 1 , Hiroyoshi Mori 1 , Matthew D Kutyna 1 , Sho Torii 1 , Atsushi Sakamoto 1 , Cheol Ung Choi 2 , Qi Cheng 1 , Megan L Grove 6 , Mariem A Sawan 3 , Yin Zhang 7 , Yihai Cao 7 , Frank D Kolodgie 1 , David P Cormode 5 , Dan E Arking 8 , Eric Boerwinkle 6, 9 , Alanna C Morrison 6 , Jeanette Erdmann 10 , Nona Sotoodehnia 11 , Renu Virmani 1 , Aloke V Finn 1, 3
Affiliation  

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.

中文翻译:

CD163+巨噬细胞促进血管生成和血管通透性并伴有动脉粥样硬化炎症

血红蛋白-触珠蛋白受体 CD163 摄入血红蛋白会产生一种独特的非泡沫细胞抗炎巨噬细胞表型,这种表型以前被认为具有动脉粥样硬化保护作用。在这里,我们揭示了这些巨噬细胞在动脉粥样硬化中的意想不到但重要的致病作用。使用人类动脉粥样硬化样本、培养细胞和晚期动脉粥样硬化小鼠模型,我们研究了斑块内出血对巨噬细胞功能(在血管生成、血管通透性、炎症和斑块进展方面)的作用。在人类动脉粥样硬化病变中,CD163 +巨噬细胞与斑块进展、微血管分布以及高水平的 HIF1α 和 VEGF-A 表达相关。我们在 CD163 +巨噬细胞包围的斑块内微血管中观察到不规则的血管内皮钙粘蛋白。在这些细胞内,通过抑制脯氨酰羟化酶激活 HIF1α,促进 VEGF 介导的斑块内血管生成、血管通透性和炎症细胞募集的增加。CD163 +巨噬细胞增加斑块内内皮 VCAM 表达和斑块炎症。具有 SNP rs7136716 纯合小等位基因的受试者的微血管密度升高,破裂的冠状动脉斑块中 CD163 的表达增加,并且人群中心肌梗死和冠心病的风险更高。因此,我们的研究结果强调了一种非脂质驱动的机制,替代性巨噬细胞通过 CD163/HIF1α/VEGF-A 途径促进斑块血管生成、渗漏、炎症和进展。
更新日期:2018-03-02
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