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

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

  • Diabetol Metab Syndr. 2025 Aug 13;17(1):328. doi: 10.1186/s13098-025-01891-6.
Haiyan Zhang 1,  LiBo Ruan 2,  Xuemei Fu 3,  Jinwen Yu 3,  Qingrong Ruan 3,  Yiyu Li 3,  Hongying Wang 3,  Heng Shao 3,  Haoran Dong 4,  Jianglan Cui 4
Affiliations

Affiliations

  • 1 Health Management Center, The First People's Hospital of Yunnan Province/The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, 650000, China.
  • 2 Department of Geriatric Medicine, The First People's Hospital of Yunnan Province/The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, 650000, China. jhy2000411@163.com.
  • 3 Department of Geriatric Medicine, The First People's Hospital of Yunnan Province/The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, 650000, China.
  • 4 Kunming University of Science and Technology, Kunming, Yunnan, 650500, China.
PMID: 40804414 DOI: 10.1186/s13098-025-01891-6
Abstract

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.

Keywords

Atherosclerosis; ICOS/ICOSL signaling; Type 2 diabetes; Vascular complications.

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