Lymphatic Endothelial Branched-Chain Amino Acid Catabolic Defects Undermine Cardiac Lymphatic Integrity and Drive HFpEF

作者：Xiong Guo, Chong Huang, Ling Zhang, Guangyu Hu, Yunhui Du, Xiyao Chen, Fangfang Sun, Tongzheng Li, Zhe Cui, Congye Li, Yongzhen Guo, Wenjun Yan, Yunlong Xia, Shan Wang, Hui Liu, Zhiyuan Liu, Zhen Lin, Xinyi Wang, Zhengyang Wang, Fuyang Zhang, Ling Tao · 发表于：Circulation · 年份：2025 · DOI：10.1161/circulationaha.124.071741 · 被引用次数：19 · 研究领域：Lymphatic System and Diseases、Cerebrospinal fluid and hydrocephalus、Lymphatic Disorders and Treatments

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) has become the most prevalent type of heart failure, but effective treatments are lacking. Cardiac lymphatics play a crucial role in maintaining heart health by draining fluids and immune cells. However, their involvement in HFpEF remains largely unexplored. METHODS: We examined cardiac lymphatic alterations in mice with HFpEF with comorbid obesity and hypertension, and in heart tissues from patients with HFpEF. Using genetically engineered mouse models and various cellular and molecular techniques, we investigated the role of cardiac lymphatics in HFpEF and the underlying mechanisms. RESULTS: In mice with HFpEF, cardiac lymphatics displayed substantial structural and functional anomalies, including decreased lymphatic endothelial cell (LEC) density, vessel fragmentation, reduced branch connections, and impaired capacity to drain fluids and immune cells. LEC numbers and marker expression levels were also decreased in heart tissues from patients with HFpEF. Stimulating lymphangiogenesis with an adeno-associated virus expressing an engineered variant of vascular endothelial growth factor C (VEGFC C156S ) that selectively activates vascular endothelial growth factor receptor 3 (VEGFR3) in LECs restored cardiac lymphatic integrity and substantially alleviated HFpEF. Through discovery-driven approaches, defective branched-chain amino acid (BCAA) catabolism was identified as a predominant metabolic signature in HFpE...