title: Cardiac lymphatics are heterogeneous in origin and respond to injury.
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.
authors.forename: Linda
authors.initials: L
authors.lastname: Klotz
authors.forename: Sophie
authors.initials: S
authors.lastname: Norman
authors.forename: Joaquim Miguel
authors.initials: JM
authors.lastname: Vieira
authors.forename: Megan
authors.initials: M
authors.lastname: Masters
authors.forename: Mala
authors.initials: M
authors.lastname: Rohling
authors.forename: Karina N
authors.initials: KN
authors.lastname: Dubé
authors.forename: Sveva
authors.initials: S
authors.lastname: Bollini
authors.forename: Fumio
authors.initials: F
authors.lastname: Matsuzaki
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Carr
authors.forename: Paul R
authors.initials: PR
authors.lastname: Riley
mesh_terms: D000818:Animals; D019070:Cell Lineage; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D006321:Heart / Q000502:physiology / Q000503:physiopathology; D018398:Homeodomain Proteins / Q000378:metabolism; D042583:Lymphangiogenesis; D042601:Lymphatic Vessels / Q000166:cytology* / Q000293:injuries* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000378:metabolism / Q000503:physiopathology; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000378:metabolism; D062211:Spatio-Temporal Analysis; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000378:metabolism; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism; D014680:Veins / Q000166:cytology; D015017:Yolk Sac / Q000166:cytology; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: D018398:Homeodomain Proteins; D051567:Proto-Oncogene Proteins c-vav; D025521:Tumor Suppressor Proteins; D042582:Vascular Endothelial Growth Factor C; C496619:Vav1 protein, mouse; D000098551:Prospero-Related Homeobox 1 Protein; D016186:Receptor, Macrophage Colony-Stimulating Factor; D020797:Receptor, Platelet-Derived Growth Factor beta; D042787:Receptor, TIE-2; C079086:Tek protein, mouse