Building the drains: the lymphatic vasculature in health and disease

Abstract

The lymphatic vasculature is comprised of a network of endothelial vessels found in close proximity to but separated from the blood vasculature. An essential tissue component of all vertebrates, lymphatics are responsible for the maintenance of fluid homeostasis, dissemination of immune cells, and lipid reabsorption under healthy conditions. When lymphatic vessels are impaired due to invasive surgery, genetic disorders, or parasitic infections, severe fluid build-up accumulates in the affected tissues causing a condition known as lymphedema. Malignant tumors can also directly activate lymphangiogenesis and use these vessels to promote the spread of metastatic cells. Although their first description goes back to the times of Hippocrates, with subsequent anatomical characterization at the beginning of the 20th-century, the lack of identifying molecular markers and tools to visualize these translucent vessels meant that investigation of lymphatic vessels fell well behind research of blood vessels. However, after years under the shadow of the blood vasculature, recent advances in imaging technologies and new genetic and molecular tools have accelerated the pace of research on lymphatic vessel development. These new tools have facilitated both work in classical mammalian models and the emergence of new powerful vertebrate models like zebrafish, quickly driving the field of lymphatic development back into the spotlight. In this review, we summarize the highlights of recent research on the development and function of the lymphatic vascular network in health and disease. WIREs Dev Biol 2016, 5:689-710. doi: 10.1002/wdev.246 For further resources related to this article, please visit the WIREs website.

Organ-specific lymphatic vasculature: From development to pathophysiology

“…Since the discovery of VEGF-C and its receptor, VEGFR3, as the key lymphangiogenic growth factor pathway and the transcription factor Prox1 as the master of LEC specification, the development of lymphatic vasculature has been extensively studied and characterized in mouse and zebrafish models ( Escobedo and Oliver, 2016 ; Venero Galanternik et al, 2016 ). The majority of LECs are produced by transdifferentiation from venous endothelium, when a subpopulation of venous ECs expressing Prox1 is specialized into LECs ( Escobedo and Oliver, 2016 ; Venero Galanternik et al, 2016 ). Importantly, recent lineage-tracing studies highlighted an unexpected diversity of LEC origins in several organs.…”

Inflammatory Manifestations of Lymphedema

“…Fluid flow through the lymphatic vasculature plays a critical role in fluid homeostasis, immunity, and lipid reabsorption [ 31 , 32 ]. When lymphatic injury is present, fluid flow is disrupted, leading to fluid accumulation, vessel distention, valve dysfunction, and reflux [ 33 , 34 ].…”

Live Imaging of Intracranial Lymphatics in the Zebrafish

“…Historically, lymphatic vessels have been thought to be excluded from the central nervous system, but several recent reports have documented the presence of lymphatic vessels in the meninges surrounding the mouse brain, particularly adjacent to dural sinuses, and have demonstrated the important function of these vessels for draining cerebrospinal fluid (CSF), their strong association with immune cells, and their importance for immune surveillance of the brain 1, 2 . Since the zebrafish provides a superb model for in vivo analysis of vascular development and function 29 and since it has a lymphatic vascular system comparable in most respects to that of mammals 30,31 , we sought to determine whether zebrafish also possess intracranial lymphatics, and whether fish could provide a valuable model for live imaging of intracranial lymphatic development and function.…”