Diminished lymphangiogenesis in pericoronary adipose tissue mediates diabetes-aggravated coronary artery atherosclerosis

Background Pericoronary adipose tissue (PCAT), due to its anatomic and functional proximity to coronary arteries, plays a crucial role in diabetes mellitus (DM)-associated coronary artery disease (CAD) progression. However, the mechanism by which PCAT mediates CAD progression remains unclear. Purpose This study aimed to investigate whether impaired lymphatic vessels in PCAT involved in pathological development of CAD under DM and explore its molecular mechanisms. Methods We included consecutive patients undergoing cardiac valve surgery (control group) and coronary artery bypass grifting surgery (CAD group) between February and September 2024. The Syntax and Gensini scores were quantified for all patients. PCAT specimens obtained intraoperatively were subjected to histological analysis. Furthermore, single-nucleus RNA sequencing (snRNA-seq) was performed to characterize intercellular communications between epicardial adipocytes and lymphatic endothelial cells (LECs). The diabetic models of human adipocytes and LECs were established using palmitic acid (PA) and high glucose (HG) in vitro to validate intercellular signaling. Results The prospective observational study enrolled 102 patients (72 males), comprising 32 controls and 70 CAD patients (including 30 DM and 40 non-DM). Compared to controls, CAD patients exhibited significantly increased adipocyte size, macrophage infiltration, and reduced lymphatic density, which were more pronounced in CAD patients with DM (Fig. 1A-E). Furthermore, CAD patients with DM exhibited more severe lesions (Fig. 1F), poorer prognosis, and higher readmission rate than non-DM. Correlation analysis revealed that the number of lymphatic vessels was negatively associated with both epicardial adipocyte size and the severity of CAD (Fig. 1G-I). snRNA-seq identified significantly diminished IGF1-IGF1R signaling between adipocytes (as source) and LECs (as target) in PCAT of CAD patients with DM (Fig. 1J). The levels of IGF1 protein in culture supernatant from PCAT of DM and human adipocyte of diabetic model were significantly lower than controls (Fig. 1K-L). Treatment with recombinant IGF1 protein effectively stimulated LEC proliferation and enhanced tube formation under diabetic condition, whereas IGF1R antagonist (AXL1717) impeded these protective effects (Fig. 1M-N). Conclusions In this work, we find pathological adipocyte hypertrophy and impaired lymphatic vessels in PCAT of CAD patients with DM. Diminished IGF1-IGF1R signaling between adipocytes-LECs interaction may be involved in lymphatic vessel impairment and DM-aggravated CAD (Fig. 2). Our work contributes to providing a novel therapeutic target for treating CAD in patients with DM.