Hyperglycemia-induced endothelial dysfunction is alleviated by thioredoxin mimetic peptides through the restoration of VEGFR-2-induced responses and improved cell survival

Diabetes mellitus is an important cardiovascular risk factor characterized by elevated plasma glucose levels. High glucose (HG) negatively influences endothelial cell (EC) function, which is characterized by the inability of ECs to respond to vascular endothelial growth factor (VEGF-A) stimulation....

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Bibliographic Details
Published in:International journal of cardiology 2020-06, Vol.308, p.73-81
Main Authors: Hemling, Pia, Zibrova, Darya, Strutz, Jasmin, Sohrabi, Yahya, Desoye, Gernot, Schulten, Henny, Findeisen, Hannes, Heller, Regine, Godfrey, Rinesh, Waltenberger, Johannes
Format: Article
Language:English
Subjects:
Angiogenesis
Cell Survival
Cells, Cultured
Chemotaxis
Diabetes
Endothelial Cells
Female
Humans
Hyperglycemia - drug therapy
Migration
Pregnancy
Thioredoxin
Thioredoxins
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factor Receptor-2
VEGFR-2
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Summary:Diabetes mellitus is an important cardiovascular risk factor characterized by elevated plasma glucose levels. High glucose (HG) negatively influences endothelial cell (EC) function, which is characterized by the inability of ECs to respond to vascular endothelial growth factor (VEGF-A) stimulation. We aimed to identify potential strategies to improve EC function in diabetes. Human umbilical cord endothelial cells (HUVECs) were subjected to hyperglycemic milieu by exposing cells to HG together with glucose metabolite, methylglyoxal (MG) in vitro. Hyperglycemic cells showed reduced chemotactic responses towards VEGF-A as revealed by Boyden chamber migration assays, indicating the development of “VEGF resistance” phenotype. Furthermore, HG/MG-exposed cells were defective in their general migratory and proliferative responses and were in a pro-apoptotic state. Mechanistically, the exposure to HG/MG resulted in reactive oxygen species (ROS) accumulation which is secondary to the impairment of thioredoxin (Trx) activity in these cells. Pharmacological and genetic targeting of Trx recapitulated VEGF resistance. Functional supplementation of Trx using thioredoxin mimetic peptides (TMP) reversed the HG/MG-induced ROS generation, improved the migration, proliferation, survival and restored VEGF-A-induced chemotaxis and sprouting angiogenesis of hyperglycemic ECs. Importantly, TMP treatment reduced ROS accumulation and improved VEGF-A responses of placental arterial endothelial cells isolated from gestational diabetes mellitus patients. Our findings suggest a putative role for Trx in modulating EC function and its functional impairment in HG conditions contribute to EC dysfunction. Supplementation of TMP could be used as a novel strategy to improve endothelial cell function in diabetes. •Impaired Trx activity related to hyperglycemia contributes to endothelial dysfunction through induction of oxidative stress.•Dysfunctional endothelial cells exhibit a “VEGF resistance” phenotype and show reduced cell surface expression of VEGFR-2.•Dysfunctional endothelial cells show reduced migration, proliferation and survival.•Thioredoxin mimetic peptides (TMP) reverse DM-induced endothelial dysfunction by alleviating oxidative stress.•Use of TMPs could be a novel strategy to improve endothelial function in diabetes.
ISSN:0167-5273
1874-1754
DOI:10.1016/j.ijcard.2019.12.065