Increased frequency of proangiogenic tunica intima endothelial kinase 2 (Tie2) expressing monocytes in individuals with type 2 diabetes mellitus
Reijrink, M; van Ark, J; Lexis, C P H; Visser, L M; Lodewijk, M E; van der Horst, I C C; Zeebregts, C J; van Goor, H; de Jager, S C A; Pasterkamp, G; Wolffenbuttel, B H R; Hillebrands, J L
(2022) Cardiovascular Diabetology, volume 21, issue 1, pp. 1 - 16
(Article)
Abstract
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
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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.
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Keywords: 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, Tie2, Macrovascular disease, Type 2 diabetes mellitus, Angiogenesis, Monocytes, Monocyte heterogeneity, Atherosclerosis, Cardiology and Cardiovascular Medicine, Internal Medicine, Endocrinology, Diabetes and Metabolism, Journal Article
ISSN: 1475-2840
Publisher: BioMed Central
Note: Funding Information: This study was supported by the Dutch Diabetes Foundation (Grant 2006.01.007). M.R. was supported by the MD/PhD program of the Graduate School of Medical Sciences (GSMS), UMCG. J.v.A. and M.R. were associated members and J.L.H. was PI of the Deutsche Forschungsgemeinschaft IRTG 1874 DIAMICOM. Funding Information: The authors would like to thank Petra J. Ottens (Surgical Research Laboratory, UMCG) for providing the Ang1 and Ang2 ELISA kits. Publisher Copyright: © 2022, The Author(s).
(Peer reviewed)