Cardiovasc Diabetol. 2026 Jan 24. doi: 10.1186/s12933-025-03054-3. Online ahead of print.
ABSTRACT
BACKGROUND: Epicardial adipose tissue (EpAT), particularly pericoronary adipose tissue (PCAT), plays a crucial role in diabetes mellitus (DM)-aggravated coronary artery disease (CAD). Emerging evidence suggests that dysfunction of the arterial lymphatic network contributes to atherosclerosis progression. Our study aimed to investigate whether lymphatic vessel impairment in PCAT (a type of EpAT) is involved in DM-related CAD and to explore its underlying molecular mechanisms.
METHODS: We prospectively enrolled patients undergoing heart valve surgery (control [CTRL] group) and coronary artery bypass grafting surgery (CAD group) between February 2024 and March 2025. EpAT volume (EpATv) and SYNTAX scores were assessed, and human PCAT samples were performed with pathological staining. Single-nucleus RNA sequencing (snRNA-seq) was employed to characterize intercellular communication between epicardial adipocytes and lymphatic endothelial cells (LECs). In vitro diabetic models of human adipocytes and LECs were established using palmitic acid (PA) and high concentration glucose (HG) to verify intercellular signaling.
RESULTS: Of a total of 160 patients enrolled (113 males), 48 were controls and 112 were CAD patients (44 with DM). CAD patients, particularly those with DM, showed increased EpATv, adipocyte size, macrophage infiltration, and reduced lymphatic vessel density. Lymphatic vessel density was inversely correlated with both adipocyte size and CAD severity. CAD patients with DM also had worse prognosis and higher readmission rates. snRNA-seq analysis revealed significantly attenuated IGF1-IGF1R signaling between epicardial adipocytes and LECs in the PCAT of CAD patients with DM. Recombinant IGF1 effectively enhanced LEC proliferation, migration, and tube formation under diabetic conditions, whereas the IGF1R antagonist impeded these protective effects.
CONCLUSIONS: Our findings demonstrate that attenuated IGF1-IGF1R signaling between epicardial adipocytes and LECs may contribute to lymphatic impairment in PCAT, which is associated with CAD progression in DM. Our work may represent a novel potential therapeutic target for CAD patients with DM.
RESEARCH INSIGHTS: What is currently known about this topic?Lymphatic vessels play a crucial role in mediating the progression of atherosclerosis. Epicardial adipose tissue (EpAT) acts as critical anatomical and functional link coupling diabetes mellitus (DM) and coronary artery disease (CAD). Adipocytes are involved in the regulation of lymphatic endothelial cell proliferation and lymphangiogenesis.What is the key research question?Whether impaired lymphatic vessels in pericoronary adipose tissue (PCAT, a type of EpAT) were involved in the pathological development of DM-related CAD.What is new?DM-aggravated CAD is associated with reduced lymphatic vessel density within PCAT. It identifies a novel intercellular signaling interaction between epicardial adipocytes and lymphatic endothelial cells in modulating lymphangiogenesis.How might this study influence clinical practice?Enhancing lymphangiogenesis through modulation of IGF1-IGF1R signaling pathway may offer new strategies for improving cardiovascular outcomes. Additionally, lymphatic vessel density in PCAT may serve as a biomarker for CAD severity and progression. This work highlights a novel potential therapeutic target for CAD patients with DM.
PMID:41580761 | DOI:10.1186/s12933-025-03054-3