Insulin Downregulates the Transcriptional Coregulator CITED2, an Inhibitor of
Proangiogenic Function in Endothelial Cells.
Authors Wang X, Lockhart SM, Rathjen T, Albadawi H, Sørensen D, O'Neill BT, Dwivedi N,
Preil SR, Beck HC, Dunwoodie SL, Watkins MT, Rasmussen LM, Rask-Madsen C
Submitted By Christian Rask-Madsen on 9/28/2016
Status Published
Journal Diabetes
Year 2016
Date Published 8/1/2016
Volume : Pages Not Specified : Not Specified
PubMed Reference 27561725
Abstract In patients with atherosclerotic complications of diabetes, impaired
neovascularization of ischemic tissue in the myocardium and lower limb limits
the ability of these tissues to compensate for poor perfusion. We identified 10
novel insulin-regulated genes, among them Adm, Cited2 and Ctgf, which were
downregulated in endothelial cells by insulin through FoxO1. CITED2, which was
downregulated by insulin by up to 54%, is an important negative regulator of
hypoxia-inducible factor (HIF) and impaired HIF signaling is a key mechanism
underlying the impairment of angiogenesis in diabetes. Consistent with
impairment of vascular insulin action, CITED2 was increased in cardiac
endothelial cells from mice with diet-induced obesity and from db/db mice and
was 3.8-fold higher in arterial tissue from patients with type 2 diabetes than
non-diabetic controls. CITED2 knockdown promoted endothelial tube formation and
endothelial cell proliferation while CITED2 overexpression impaired HIF activity
in vitro After femoral artery ligation, induction of an endothelial-specific HIF
target gene in hindlimb muscle was markedly upregulated in mice with endothelial
cell deletion of CITED2, suggesting that CITED2 can limit HIF activity in vivo
We conclude that vascular insulin resistance in type 2 diabetes contributes to
the upregulation of CITED2 which impairs HIF signaling and endothelial
pro-angiogenic function.

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