Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Lineage
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Endothelial Cells / cytology
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Endothelial Cells / metabolism
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Female
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Heart / physiology
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Heart / physiopathology
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Homeodomain Proteins / metabolism
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Lymphangiogenesis*
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Lymphatic Vessels / cytology*
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Lymphatic Vessels / injuries*
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Lymphatic Vessels / metabolism
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Male
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Mice
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Mice, Inbred C57BL
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Myocardial Infarction / metabolism
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Myocardial Infarction / physiopathology
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Myocardium / cytology*
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Myocardium / metabolism
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Proto-Oncogene Proteins c-vav / metabolism
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Receptor, Macrophage Colony-Stimulating Factor / metabolism
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Receptor, Platelet-Derived Growth Factor beta / metabolism
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Receptor, TIE-2 / metabolism
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Spatio-Temporal Analysis
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Tumor Suppressor Proteins / deficiency
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Tumor Suppressor Proteins / metabolism
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Vascular Endothelial Growth Factor C / metabolism
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Veins / cytology
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Yolk Sac / cytology
Substances
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Homeodomain Proteins
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Proto-Oncogene Proteins c-vav
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Tumor Suppressor Proteins
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Vascular Endothelial Growth Factor C
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Vav1 protein, mouse
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prospero-related homeobox 1 protein
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Receptor, Macrophage Colony-Stimulating Factor
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Receptor, Platelet-Derived Growth Factor beta
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Receptor, TIE-2
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Tek protein, mouse