The evolving cardiac lymphatic vasculature in development, repair and regeneration

Abstract

The lymphatic vasculature has an essential role in maintaining normal fluid balance in tissues and modulating the inflammatory response to injury or pathogens. Disruption of normal development or function of lymphatic vessels can have severe consequences. In the heart, reduced lymphatic function can lead to myocardial oedema and persistent inflammation. Macrophages, which are phagocytic cells of the innate immune system, contribute to cardiac development and to fibrotic repair and regeneration of cardiac tissue after myocardial infarction. In this Review, we discuss the cardiac lymphatic vasculature with a focus on developments over the past 5 years arising from the study of mammalian and zebrafish model organisms. In addition, we examine the interplay between the cardiac lymphatics and macrophages during fibrotic repair and regeneration after myocardial infarction. Finally, we discuss the therapeutic potential of targeting the cardiac lymphatic network to regulate immune cell content and alleviate inflammation in patients with ischaemic heart disease.

Fig. 1. Structure and function of cardiac lymphatic vessels.

a | Schematic illustration of the mediastinal lymph nodes, where the cardiac lymphatics drain the lymph. b | Dorsal and ventral aspects of the adult mouse cardiac lymphatic network. c | The path of the lymph begins at the initial lymphatics, where lymphatic endothelial cells (LECs) connected by permeable button-like junctions drain immune cells, fluids, macromolecules and pathogens from the interstitial space, making up the lymph. The lymph is transported through the pre-collector and collector that are connected by impermeable zipper junctions to the mediastinal lymph nodes.

Fig. 2. Origin and development of the mouse cardiac lymphatic vasculature.

a | The cardiac lymphatic vasculature is visible at the dorsal and ventral side of the forming mouse heart from embryonic day (E) 14.5. b–d | Different cell lineages contribute to the generation of cardiac lymphatic endothelial cells. A subpopulation of paraxial mesoderm-derived venous endothelial cells bud from the cardinal vein to give rise to lymphatic endothelium (panel b). Other non-venous populations contribute to the cardiac lymphatics, such as the yolk sac-derived haemogenic endothelium (panel c) and an Isl1⁺ second heart field population that is found specifically on the ventral cardiac lymphatics (panel d). L, left; R, right.

Fig. 3. Endogenous and VEGFC-C156S-augmented cardiac lymphatic response to myocardial infarction.

Schematic illustration of the endogenous response of the lymphatic vessels to myocardial infarction and the augmented response induced by administration of vascular endothelial growth factor C (VEGFC)-C156S. a | After induction of myocardial infarction through surgical ligation of the left anterior descending coronary artery, accumulation of fluids leads to oedema and infiltration of immune cells, such as macrophages, dendritic cells and T cells, into the myocardium. b | In response to myocardial infarction, cardiac lymphatic vessels undergo lymphangiogenesis in an attempt to clear the excessive tissue fluid and the inflammatory cells. However, this response is insufficient and the heart is repaired through fibrotic scar formation. c | Augmentation of the lymphangiogenic response through administration of VEGFC-C156S leads to decreased oedema and increased immune cell clearance and subsequently to improved cardiac healing and function.