SAT-588 Organ-specific Stress Responses Of Vascular Endothelial Cells Revealed By Single-cell Analysis

Abstract Disclosure: M. Shiina: None. M. Yokoyama: None. T. Tanaka: None. A. Nakayama: None. The contribution of vascular endothelial cells to lifestyle- related diseases and aging-related diseases is widely recognized. Although aging and obesity are systemic conditions, their pathological effects vary by organ. Based on this background, we hypothesized that endothelial cells exhibit organ-specific stress responses. To investigate this, we performed single-cell RNA sequencing on endothelial cells isolated from key metabolism-related mouse organs: adipose tissue, heart, skeletal muscle, and liver.In this study, our purpose was to elucidate organ-specific molecular changes in endothelial cells under aging and obesity stress, with a focus on transcription factors (TFs) regulating these changes. We identified significantly differentially expressed genes (DEGs), especially the top 100 upregulated genes in each condition. To interpret their functions, we used scGSVA to visualize pathway activity at the single-cell level. For TF analysis, we applied SCENIC, which infers regulatory activity based on co-expression between TFs and their target genes. TFs were ranked based on activation scores in both conditions. By integrating DEGs and TFs, we construct stress-related regulatory networks.Under aging stress, we observed a shared response across organs, activation of interferon (IFN) signaling pathways. These pathways promote immune defense via IFN production. Despite organ-specific gene expression, IFN pathway activation was a consistent functional feature. Additionally, TF analysis revealed that aging-related expression changes were commonly regulated by IFN-related TFs (Irf7, Irf9, Stat1, Stat2) in all organs. Thus, both pathway and TF analyses consistently support IFN pathway activation as a hallmark of aging stress.In contrast, obesity stress has induced distinct organ-specific responses:•Adipose tissue: Activation of fatty acid metabolism•Heart: Vascular function and cell signaling changes•Skeletal muscle: Enhanced antioxidant activity and protein synthesis•Liver: Altered energy metabolism and ion channel regulationTFs involved in obesity responses showed little overlap across organs. Although Pparg was activated in adipose tissue, muscle, and liver, its regulon targets varied, suggesting that even shared TFs may exhibit organ-specific regulatory functions depending on the cellular context. Presentation: Saturday, July 12, 2025