Abstract Body: Myocardial infarction (MI) remains a leading cause of death worldwide. Inflammatory responses after MI are known to impact cardiac disease resolution and contribute to the progression of heart failure. Cardiac lymphatics play a key role in inflammatory resolution after MI, allowing for tissue repair to proceed. Recent work has highlighted the importance of cardiac lymphatics in cardiac repair including immune resolution, and cardio protection by paracrine signals. However, post-MI cardiac lymphatics in rodent models or MI patients exhibit abnormal lymphatic drainage with dilated and leaky lymphatics, suggesting cellular and molecular changes during MI impact the structure and function of cardiac lymphatics. However, underlying mechanisms leading to these changes remain unclear. Transforming growth factor beta (TGFβ), is a known regulator of cardiac fibrosis and endothelial dysfunction after MI. However, whether TGFβ signaling affects post-MI cardiac lymphangiogenesis and lymphatic function is unknown. My work shows that lymphatic endothelial cell (LEC)-specific TGFβR2 deficient mice (TGFβR2^ΔLEC/ΔLEC mice) display improved post-MI cardiac function with reduced cardiac fibrosis. Immunostaining reveals significantly increased lymphangiogenesis and reduced macrophage accumulation in post-MI hearts of these mutant mice, strongly suggesting a functional role of TGFβ in regulating post-MI cardiac lymphangiogenesis and cardiac function. Mechanistically, I found that LECs treated with TGFβ showed significantly reduced proliferation, increased apoptosis, disrupted junction and cytoskeleton organization, as well as reduced migration. RNAseq analysis showed enriched metabolic pathways, with significant downregulation of genes related to Fatty-Acid Oxidation (FAO) in TGFβ treated LECs. Among those, CPT1A expression, the rate limiting enzyme of FAO previously reported to be critical for embryonic lymphangiogenesis, was significantly downregulated. Enhancing CPT1A function rescued TGFβ mediated LEC activities in vitro, suggesting TGFβ negatively regulates LEC activities by downregulating CPT1A and CPT1A-mediated FAO in LECs. These data provide strong evidence that TGFβ signaling modulates LEC metabolism to impede lymphangiogenesis and promote cardiac dysfunction following MI, and inhibition of TGFβ signaling in LECs could provide a novel therapeutic strategy to improve lymphatic vascular integrity and lymphangiogenesis, improving cardiac function following MI.