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Background <p>Type 2 diabetes mellitus (T2DM) is often complicated by vascular conditions such as atherosclerosis, which contribute significantly to morbidity and mortality. The ICOS/ICOSL signaling pathway has emerged as a promising target for mitigating these complications. This study aims to investigate the effects of ICOS/ICOSL pathway blockade on vascular inflammation and endothelial dysfunction in T2DM and atherosclerosis, and to assess its potential for clinical translation.</p> Methods <p>Peripheral blood mononuclear cells (PBMCs) were collected from T2DM patients, with and without atherosclerosis (AS), as well as healthy controls. ICAM-1 and VCAM-1 levels were measured by ELISA, and RNA sequencing was conducted to identify differentially expressed genes. In an animal model, diabetic mice were treated with ICOS-Fc fusion protein to block ICOS/ICOSL signaling. Endothelial dysfunction was modeled in mouse C166 cells and primary Human Umbilical Vein Endothelial Cells (HUVECs) using high glucose (HG), and the effects of ICOS-Fc on cell migration, angiogenesis, ROS production, apoptosis, and key signaling molecules were analyzed.</p> Results <p>ICAM-1 and VCAM-1 levels were significantly elevated in both the T2DM and AS groups compared to controls. In vivo, treatment with ICOS-Fc not only reduced the expression of ICOS, ICOSL, ICAM-1, and VCAM-1 in the aortic tissue of diabetic mice but also significantly ameliorated hyperlipidemia and reduced atherosclerotic plaque burden. In HG-treated C166 cells, ICOS-Fc reduced ROS production and apoptosis while enhancing cell migration and angiogenesis. Crucially, in HUVECs, ICOS-Fc treatment reversed HG-induced inflammatory gene expression and restored angiogenic capacity, a benefit associated with the normalization of endothelial nitric oxide synthase (eNOS) phosphorylation.</p> Conclusion <p>Blocking the ICOS/ICOSL signaling pathway effectively mitigates vascular inflammation and endothelial dysfunction in T2DM with atherosclerosis. These findings suggest that targeting this pathway holds promise as a novel therapeutic strategy for managing vascular complications in T2DM.</p>

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Mechanisms and clinical translation of ICOS/ICOSL signaling pathway blockade in delaying vascular complications of type 2 diabetes

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月13日

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  • Haiyan Zhang,
  • LiBo Ruan,
  • Xuemei Fu,
  • Jinwen Yu,
  • Qingrong Ruan,
  • Yiyu Li,
  • Hongying Wang,
  • Heng Shao,
  • Haoran Dong,
  • Jianglan Cui

摘要

Background

Type 2 diabetes mellitus (T2DM) is often complicated by vascular conditions such as atherosclerosis, which contribute significantly to morbidity and mortality. The ICOS/ICOSL signaling pathway has emerged as a promising target for mitigating these complications. This study aims to investigate the effects of ICOS/ICOSL pathway blockade on vascular inflammation and endothelial dysfunction in T2DM and atherosclerosis, and to assess its potential for clinical translation.

Methods

Peripheral blood mononuclear cells (PBMCs) were collected from T2DM patients, with and without atherosclerosis (AS), as well as healthy controls. ICAM-1 and VCAM-1 levels were measured by ELISA, and RNA sequencing was conducted to identify differentially expressed genes. In an animal model, diabetic mice were treated with ICOS-Fc fusion protein to block ICOS/ICOSL signaling. Endothelial dysfunction was modeled in mouse C166 cells and primary Human Umbilical Vein Endothelial Cells (HUVECs) using high glucose (HG), and the effects of ICOS-Fc on cell migration, angiogenesis, ROS production, apoptosis, and key signaling molecules were analyzed.

Results

ICAM-1 and VCAM-1 levels were significantly elevated in both the T2DM and AS groups compared to controls. In vivo, treatment with ICOS-Fc not only reduced the expression of ICOS, ICOSL, ICAM-1, and VCAM-1 in the aortic tissue of diabetic mice but also significantly ameliorated hyperlipidemia and reduced atherosclerotic plaque burden. In HG-treated C166 cells, ICOS-Fc reduced ROS production and apoptosis while enhancing cell migration and angiogenesis. Crucially, in HUVECs, ICOS-Fc treatment reversed HG-induced inflammatory gene expression and restored angiogenic capacity, a benefit associated with the normalization of endothelial nitric oxide synthase (eNOS) phosphorylation.

Conclusion

Blocking the ICOS/ICOSL signaling pathway effectively mitigates vascular inflammation and endothelial dysfunction in T2DM with atherosclerosis. These findings suggest that targeting this pathway holds promise as a novel therapeutic strategy for managing vascular complications in T2DM.