Cardiac Lymphatics Are Heterogeneous in Origin and Respond to Injury

Nature. 2015 Jun 4;522(7554):62-7. doi: 10.1038/nature14483.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Homeodomain Proteins
  • Proto-Oncogene Proteins c-vav
  • Tumor Suppressor Proteins
  • Vascular Endothelial Growth Factor C
  • Vav1 protein, mouse
  • prospero-related homeobox 1 protein
  • Receptor, Macrophage Colony-Stimulating Factor
  • Receptor, Platelet-Derived Growth Factor beta
  • Receptor, TIE-2
  • Tek protein, mouse