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Leung, Oscar M.; Li, Jiatao; Li, Xisheng; Chan, Vicken W.; Yang, Kevin Y.; Ku, Manching; Ji, Lu; Sun, Hao; Waldmann, Herman; Tian, Xiao Yu; Huang, Yu; Lau, James; Zhou, Bin; Lui, Kathy O.
Cell reports (Cambridge), 08/2018, Letnik: 24, Številka: 6Journal Article
The role of CD4+ T cells in the ischemic tissues of T2D patients remains unclear. Here, we report that T2D patients’ vascular density was negatively correlated with the number of infiltrating CD4+ T cells after ischemic injury. Th1 was the predominant subset, and Th1-derived IFN-γ and TNF-α directly impaired human angiogenesis. We then blocked CD4+ T cell infiltration into the ischemic tissues of both Leprdb/db and diet-induced obese T2D mice. Genome-wide RNA sequencing shows an increased proliferative and angiogenic capability of diabetic ECs in ischemic tissues. Moreover, wire myography shows enhanced EC function and laser Doppler imaging reveals improved post-ischemic blood reperfusion. Mechanistically, functional revascularization after CD4 coreceptor blockade was mediated by Tregs. Genetic lineage tracing via Cdh5-CreER and Apln-CreER and coculture assays further illustrate that Tregs increased vascular density and induced de novo sprouting angiogenesis in a paracrine manner. Taken together, our results reveal that Th1 impaired while Tregs promoted functional post-ischemic revascularization in obesity and diabetes. Display omitted •More CD4+ T cells and fewer Tregs are found in T2D patients with PAD•CD4+ Th1 cells inhibit de novo sprouting angiogenesis in T2D•IFN-γ and TNF-α inhibit endothelial cell function•IL-10 and amphiregulin promote endothelial cell proliferation and function There are significantly more CD4+ Th1 cells but fewer regulatory T cells (Tregs) in ischemic tissues from T2D patients than from normoglycemic patients with peripheral artery disease. Leung et al. show that Th1 cells impair vascular regeneration in T2D individuals in a paracrine manner, while Tregs potentiate regeneration.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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