de la Cruz, EsterCadenas, VanessaTemiño, SusanaOliver, GuillermoTorres, Miguel2025-07-162025-07-162025-06EMBO Rep. 2025 Jun;26(11):2803-2818.https://hdl.handle.net/20.500.12105/26834The contractile ability of the mammalian heart critically relies on blood coronary circulation, essential to provide oxygen and nutrients to myocardial cells. In addition, the lymphatic vasculature is essential for the myocardial immune response, extracellular fluid homeostasis and response to injury. Recent studies identified different origins of coronary lymphatic endothelial cells, however, the cues that govern coronary lymphangiogenesis remain unknown. Here we show that the coronary lymphatic vasculature develops in intimate contact with the epicardium and with epicardial-derived cells. The epicardium expresses the lymphangiogenic cytokine VEGFC and its conditional deletion in the epicardium abrogates coronary lymphatic vasculature development. Interestingly, VEGFD is also expressed in the epicardium and cooperates with VEGFC in coronary lymphangiogenesis, but it does so only in females, uncovering an unsuspected sex-specific role for this cytokine. These results identify the epicardium/subepicardium as a signaling niche required for coronary lymphangiogenesis and VEGFC/D as essential mediators of this role.We thank Cristina Villa and the Torres group for helpful comments and discussions, Xiaolei Liu and Michael Oxendine for advice during experimentation, Wanshu Ma for the Eef1a1VegfcGOF mouse strain, Wanshu Ma and Mark Kahn for the Vegfcflox/flox mouse, and the CNIC Genomics, Microscopy, Cellomics and Transgenesis Units personnel for their support to this work. This work was supported by the European Commission H2020 Program grant SC1- BHC-07-2019. Ref. 874764 “REANIMA” to MT; the Spanish Ministerio de Ciencia e Innovación grant PGC2018-096486-B-I00 to MT; Grant TNE17CVD04 from the Leducq Foundation to MT; Comunidad de Madrid grant P2022/BMD-7245 to MT; RO1HL151388 and RO1HL162800 to GO, FPU grant from the Spanish Ministry of Education, Culture and Sports (Grant FPU15/ 02955) and EMBO Short-Term Fellowship number 8357 to EdC; for experiments in the Unidad de Microscopía e Imagen Dinámica, CNIC, ICTSReDib, MCIN/AEI /10.13039/501100011033 and FEDER “Una manera de hacer Europa” (#ICTS-2018-04-CNIC-16). The CNIC is supported by the Ministerio de Ciencia e Innovación and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (Grant number CEX2020-001041-S funded by MICIU/ AEI/10.13039/501100011033).engVoRhttp://creativecommons.org/licenses/by/4.0/Coronary VasculatureHeart DevelopmentLymphatic VasculatureSex-specific Gene FunctionVascular BiologyAttribution 4.0 International40128409EMBO Reportsopen access