Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 128, Issue 3, Pages 1106-1124Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI93025
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Funding
- CVPath Institute
- Woodruff Sciences Health Center at Emory University
- Carlyle Fraser Heart Center at Emory Hospital Midtown
- CardioVascular Research Foundation (CVRF) of Korea
- National Heart, Lung, and Blood Institute (NHLBI) [HL111089]
- NHLBI, NIH, Department of Health and Human Services [HHSN268201700001I, HHSN268201700003I, HHSN268201700005I, HHSN268201700004I, HHSN2682017000021]
- NIH through the American Recovery and Reinvestment Act (ARRA) [5RC2HL102419]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL111089, RC2HL102419] Funding Source: NIH RePORTER
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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 HIF1 alpha and VEGF-A expression. We observed irregular vascular endothelial cadherin in intraplaque microvessels surrounded by CD163(+) macrophages. Within these cells, activation of HIF1 alpha. 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/HIF1 alpha/VEGF-A pathway.
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