de la Cruz Ester, Cadenas Vanessa, Temiño Susana, Oliver Guillermo, Torres Miguel
Cardiovascular Regeneration Program, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, 28029, Spain.
Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain.
EMBO Rep. 2025 Mar 24. doi: 10.1038/s44319-025-00431-7.
The 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.
哺乳动物心脏的收缩能力严重依赖于冠脉循环，冠脉循环对于向心肌细胞提供氧气和营养物质至关重要。此外，淋巴管系统对于心肌免疫反应、细胞外液稳态及损伤反应也必不可少。近期研究确定了冠状淋巴管内皮细胞的不同起源，然而，调控冠状淋巴管生成的线索仍不清楚。在此我们表明，冠状淋巴管系统与心外膜及心外膜衍生细胞紧密接触发育。心外膜表达淋巴管生成细胞因子VEGFC，其在心外膜中的条件性缺失会消除冠状淋巴管系统的发育。有趣的是，VEGFD也在心外膜中表达，并在冠状淋巴管生成中与VEGFC协同作用，但仅在雌性中如此，这揭示了这种细胞因子出人意料的性别特异性作用。这些结果确定心外膜/心外膜下层是冠状淋巴管生成所需的信号微环境，且VEGFC/D是这一作用的关键介质。
