Abstract Body: The lymphatic system is a blind-ended drainage system present in almost every organ, run alongside the blood system, and it is an organ-specific network. After myocardial infarction (MI), the lymphatic circulation overseeds the blood circulation in the forming scar; this process runs in parallel with and is fundamental during the innate immunity response. The newly formed lymphatic vessels (LVs) persist in the mature scar, creating an imbalance between blood and lymphatic circulation. Physiologically, the number of LVs is lower than that of blood vessels, and the number of lymphatic endothelial cells (LECs) does not justify the heightened new lymphangiogenesis after MI. Therefore, the aim of this study is to identify the source of new LECs with a focus on the autologous contribution of LECs to the new lymphangiogenesis. Cell-to-cell and paracrine communications of LECs in physiological and pathological conditions are mostly unknown, and whether the paracrine activity of activated LECs influence other cells’ biology like endothelial cells and pericytes, has not been studied yet. To investigate the involvement of LECs’ paracrine system in endothelial cell switching, we we isolated small extracellular vesicles (sEVs) from LECs’ conditioned media. Characterization of the exosomal cargo via mass spectrometry showed that LECs-derived sEVs are enriched in bCatenin, WNT, and Frizzled, suggesting that the WNT pathway is essential for maintaining the LECs phenotype. In vivo, injection of LECs-derived sEVs in uninjured mouse hearts increased lymphangiogenesis, and in vitro preliminary data showed that blood endothelial cells treated with LECs-derived sEVs can be transcriptionally reprogrammed into the lymphatic lineage, upregulating the major lymphatic markers such as Prox-1, Lyve-1, VEGFR-3, and Podoplanin via WNT and SOX-17 signaling pathway. Interestingly, after MI, blood endothelial cells and pericytes, de novo expressed Prox-1 and lyve-1 markers in the scar and border zone area, meaning that they can acquire a LECs’ phenotype under specific conditions. Based on these data, blood endothelial cells and pericytes can be transcriptionally reprogrammed and may contribute to new lymphangiogenesis after MI