Regulatory T Cells Promote Apelin-Mediated Sprouting Angiogenesis in Type 2 Diabetes

Oscar M. Leung, Jiatao Li, Xisheng Li, Vicken W. Chan, Kevin Y. Yang, Manching Ku, Lu Ji, Hao Sun, Herman Waldmann, Xiao Yu Tian, Yu Huang, James Lau, Bin Zhou, Kathy O. Lui

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

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. 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.

Original languageEnglish (US)
Pages (from-to)1610-1626
Number of pages17
JournalCell Reports
Volume24
Issue number6
DOIs
StatePublished - Aug 7 2018

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Keywords

  • CD4 coreceptor blockade
  • CD4 regulatory T cells
  • apelin
  • type 2 diabetes
  • vascular function
  • vascular inflammation
  • vascular regeneration

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Leung, O. M., Li, J., Li, X., Chan, V. W., Yang, K. Y., Ku, M., Ji, L., Sun, H., Waldmann, H., Tian, X. Y., Huang, Y., Lau, J., Zhou, B., & Lui, K. O. (2018). Regulatory T Cells Promote Apelin-Mediated Sprouting Angiogenesis in Type 2 Diabetes. Cell Reports, 24(6), 1610-1626. https://doi.org/10.1016/j.celrep.2018.07.019