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Updated: Jun 15, 2025
Epicardial Outgrowth Culture Assay and Ex Vivo Assessment of Epicardial-derived Cell Migration
Published on: March 18, 2016
Epicardial VEGFC/D signaling is essential for coronary lymphangiogenesis
Ester de la Cruz1, Vanessa Cadenas1,2, Susana Temiño1,2
1Cardiovascular Regeneration Program, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, 28029, Spain.
Insights
The epicardium is crucial for heart lymphatic vessel development, expressing key growth factors. This study reveals the epicardium
Area of Science:
- Cardiovascular Biology
- Developmental Biology
- Lymphatic Research
Background:
- Coronary circulation is vital for heart function, supplying oxygen and nutrients.
- The heart's lymphatic vasculature plays roles in immunity, fluid balance, and injury response.
- The developmental origins of coronary lymphatics are known, but the signaling cues remain unclear.
Purpose of the Study:
- To investigate the signaling mechanisms governing coronary lymphangiogenesis.
- To identify the cellular origins and signaling niches involved in heart lymphatic development.
Main Methods:
- Conditional gene deletion in epicardial cells.
- Analysis of coronary lymphatic vasculature development in mouse models.
- Investigating the roles of Vascular Endothelial Growth Factor C (VEGFC) and VEGFD.
Main Results:
- Coronary lymphatic vasculature develops in close association with the epicardium.
- Epicardial expression of VEGFC is essential for coronary lymphatic development.
- VEGFD, also expressed by the epicardium, cooperates with VEGFC in lymphangiogenesis, exhibiting a female-specific role.
- Epicardium/subepicardium identified as a critical signaling niche.
Conclusions:
- The epicardium is a key signaling center regulating coronary lymphangiogenesis.
- VEGFC and VEGFD are essential mediators of epicardial signaling in heart lymphatic development.
- A novel sex-specific function of VEGFD in female coronary lymphangiogenesis was uncovered.
Abstract:
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.
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