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The lymphatic vasculature is a blind-ended network crucial for tissue-fluid homeostasis, immune surveillance and lipid absorption from the gut. Recent evidence has proposed an entirely venous-derived mammalian lymphatic system. By contrast, here we show that cardiac lymphatic vessels in mice have a heterogeneous cellular origin, whereby formation of at least part of the cardiac lymphatic network is independent of sprouting from veins. Multiple Cre–lox-based lineage tracing revealed a potential contribution from the putative haemogenic endothelium during development, and discrete lymphatic endothelial progenitor populations were confirmed by conditional knockout of Prox1 in Tie2+ and Vav1+ compartments. In the adult heart, myocardial infarction promoted a significant lymphangiogenic response, which was augmented by treatment with VEGF-C, resulting in improved cardiac function. These data prompt the re-evaluation of a century-long debate on the origin of lymphatic vessels and suggest that lymphangiogenesis may represent a therapeutic target to promote cardiac repair following injury.

Original publication

DOI

10.1038/nature14483

Type

Journal article

Journal

Nature

Publication Date

04/06/2015

Volume

522

Pages

62 - 67

Keywords

Animals, Cell Lineage, Endothelial Cells, Female, Heart, Homeodomain Proteins, Lymphangiogenesis, Lymphatic Vessels, Male, Mice, Mice, Inbred C57BL, Myocardial Infarction, Myocardium, Proto-Oncogene Proteins c-vav, Receptor, Macrophage Colony-Stimulating Factor, Receptor, Platelet-Derived Growth Factor beta, Receptor, TIE-2, Spatio-Temporal Analysis, Tumor Suppressor Proteins, Vascular Endothelial Growth Factor C, Veins, Yolk Sac