Abstract 1071: TGFβ Signaling Negatively Regulates Cardiac Lymphangiogenesis Following Myocardial Ischemia

Abstract

Cardiovascular disease is the leading cause of death worldwide. Despite high prevalence, standard treatments have made little progress, and developing novel therapeutic treatments to improve cardiac diseases is the top priority of the field. Lymphatics are essential in maintaining tissue-fluid homeostasis, clearing cell debris, and trafficking immune cells. Over recent years, cardiac lymphatics have emerged as a potential target for treatment of cardiovascular diseases, as therapeutic lymphangiogenesis is shown to improve cardiac function following myocardial infarction (MI). However, pathologic lymphangiogenesis induced by MI is reported to be dysfunctional, suggesting cellular or molecular changes occurring in MI directly impact the structure and function of cardiac lymphatics. However, the underlying mechanisms leading to these changes have not been fully explored. In this study we propose TGFβ, a profibrotic signaling molecule increased in ischemic heart diseases, negatively regulates cardiac lymphangiogenesis and lymphatic function following MI. We generated mice with conditional deletion of TGFβ receptor in Lymphatic endothelial cells (LECs) and found that these conditional null (LEC-DKO) mice showed improved post-MI cardiac function and increased lymphangiogenesis compared to controls. Mechanistically, we found that LECs with TGFβ treatment showed increased Endothelial to Mesenchymal Transition (EndMT), and impaired junction integrity. Bulk RNAseq results confirmed these findings as genes involved in EndMT were highly upregulated, and LEC marker related genes were significantly downregulated in LECs in the presence of TGFβ. More importantly, GSEA revealed metabolic reprogramming in LECs treated with TGFβ, with significantly increased expression in glycolysis related genes, but significant downregulation of genes related to fatty acid oxidation. These data provide a possible mechanism by which TGFβ signaling induces LEC metabolic switch 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, thereby improving cardiac function following MI.