Increased frequency of proangiogenic tunica intima endothelial kinase 2 (Tie2) expressing monocytes in individuals with type 2 diabetes mellitus

Cardiovasc Diabetol. 2022 May 12;21(1):72. doi: 10.1186/s12933-022-01497-6.


Background: Individuals with type 2 diabetes mellitus (T2DM) have an increased risk for developing macrovascular disease (MVD) manifested by atherosclerosis. Phenotypically and functionally different monocyte subsets (classical; CD14++CD16-, non-classical; CD14+CD16++, and intermediate; CD14++CD16+) including pro-angiogenic monocytes expressing Tie2 (TEMs) can be identified. Here we investigated monocyte heterogeneity and its association with T2DM and MVD.

Methods: Individuals with (N = 51) and without (N = 56) T2DM were recruited and allocated to "non-MVD" or "with MVD" (i.e., peripheral or coronary artery disease) subgroups. Blood monocyte subsets were quantified based on CD14, CD16 and Tie2 expression levels. Plasma levels of Tie2-ligands angiopoietin-1 and angiopoietin-2 were determined using ELISA. Carotid endarterectomy samples from individuals with (N = 24) and without (N = 22) T2DM were stained for intraplaque CD68+ macrophages (inflammation) and CD34+ (angiogenesis), as plaque vulnerability markers.

Results: Monocyte counts were similar between individuals with T2DM and healthy controls (non-diabetic, non-MVD). Non-classical monocytes were reduced (p < 0.05) in T2DM, whereas the percentage of TEMs within the intermediate subset was increased (p < 0.05). T2DM was associated with increased angiopoietin-1 (p < 0.05) and angiopoietin-2 (p = 0.0001) levels. Angiopoietin-2 levels were higher in T2DM individuals with MVD compared with non-MVD (p < 0.01). Endarterectomized plaques showed no differences in macrophage influx and microvessel number between individuals with and without T2DM.

Conclusions: Monocyte subset distribution is altered in T2DM with reduced non-classical monocytes and increased TEM percentage in the intermediate monocyte subset. Increased angiopoietin-2 levels together with increased frequency of TEMs might promote plaque vulnerability in T2DM which could however not be confirmed at tissue level in advanced atherosclerotic lesions.

Keywords: Angiogenesis; Atherosclerosis; Macrovascular disease; Monocyte heterogeneity; Monocytes; Tie2; Type 2 diabetes mellitus.

MeSH terms

  • Angiopoietin-1 / metabolism
  • Angiopoietin-2 / metabolism
  • Atherosclerosis* / metabolism
  • Diabetes Mellitus, Type 2* / metabolism
  • Humans
  • Monocytes / metabolism
  • Plaque, Atherosclerotic* / pathology
  • Receptor, TIE-2
  • Tunica Intima / chemistry
  • Tunica Intima / metabolism
  • Tunica Intima / pathology


  • Angiopoietin-1
  • Angiopoietin-2
  • Receptor, TIE-2
  • TEK protein, human