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Lymphatic vasculature development

Nature Reviews Immunology volume 4, pages 35–45 (2004)Cite this article

Key Points

  • The lymphatic system is vital for maintaining the colloid osmotic volume (or pressure) and for absorbing lipids from the intestinal tract. The lymphatic system is also essential for the immune response to infectious agents, and during cancer progression; metastatic spreading of malignant cells occurs through the lymphatic and blood vessels.

  • Lymphangiogenesis is the growth of the lymphatic vessels, and congenital or acquired dysfunction of the lymphatic system can result in the formation of lymphoedema — a disorder that results in thickening of the skin and accumulation of adipose tissue.

  • The working model for lymphatic vasculature development proposes that blood venous endothelial cells are the ground condition from which a lymphatic endothelial cell phenotype will be progressively acquired by the stepwise expression of different gene products. In this model, expression of the transcription factor prospero-related homeobox 1 (Prox1) by venous endothelial cells is sufficient to initiate the programme that leads to lymphatic endothelial cell-type specification, and lack of Prox1 activity represses the whole programme of lymphatic differentiation.

  • Nonsense mutations in vascular endothelial growth-factor receptor 3 (VEGFR3) have been identified in patients with hereditary lymphoedema and its ligand, VEGFC, was identified as a potent inducer of lymphatic sprouting. Overexpression of VEGFC through the use of a recombinant adenovirus promotes therapeutic lymphangiogenesis in a rabbit model of acquired lymphoedema as well as tumour lymphangiogenesis. Mutations in the forkhead transcription factor FOXC2 have been identified in patients with lymphoedema–distichiasis syndrome.

  • Other available mouse models with lymphatic vasculature alterations include: podoplanin-deficient mice, which have lymphatic defects associated with diminished lymphatic transport, congenital lymphoedema and dilation of lymphatic vessels; neuropilin-2-deficient mice show an absence or severe reduction in the number of small lymphatic vessels and capillaries; and functional inactivation of angiopoietin 2 indicated that this molecule is required for postnatal blood vascular remodelling and proper development of the lymphatic vasculature.

Abstract

Although the process of blood vasculature formation has been well documented, little is known about lymphatic vasculature development, despite its importance in normal and pathological conditions. The lack of specific lymphatic markers has hampered progress in this field. However, the recent identification of genes that participate in the formation of the lymphatic vasculature denotes the beginning of a new era in which better diagnoses and therapeutic treatment(s) of lymphatic disorders could become a reachable goal.

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Figure 1: Blood vascular development.
Figure 2: Human lymphatic system.
Figure 3: Sequential growth of lymphatic vessels in the mammalian embryo.
Figure 4: Model for differentiation of the lymphatic vasculature.
Figure 5: Prox1 is a specific marker for lymphatic endothelial cells.
Figure 6: Specification of lymphatic endothelial cells.

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Acknowledgements

I thank J. Wigle and N. Harvey, whose outstanding work in my laboratory has been instrumental in the progress of many of the ideas presented here, J. Morgan and S. Rockson for help with the figures, N. Harvey for critical reading of the manuscript and A. McArthur for scientific editing. This work was supported by the National Institutes of Health, Cancer Center Support from the National Cancer Institute and the American Lebanese Syrian Associated Charities (ALSAC).

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  1. Department of Genetics, St Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, 38105, Tennessee, USA

    Guillermo Oliver

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  1. Guillermo Oliver
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DATABASES

LocusLink

Ang1

Ang2

β-chemokine receptor D6

desmoplakin

FOXC2

Lyve1

Nrp2

podoplanin

Prox1

SLC

SOX18

Tie2

VEGFC

VEGFD

VEGFR2

VEGFR3

FURTHER INFORMATION

Lymphatic Research Foundation

Glossary

LYMPHANGIOGENESIS

The growth of lymphatic vessels.

LYMPHOEDEMA

Occlusion of lymphatic drainage followed by the abnormal accumulation of interstitial fluid and swelling in the affected body part.

LYMPHATIC METASTASIS

Invasion of detaching primary tumour cells through the lymphatic system to lymph nodes. After re-entering of the lymphatic vessels into the blood vasculature, tumour cells will also spread to distant organs.

PERICYTES

Smooth-muscle-like cells that cover the outer surface of the endothelial cells of blood vessels.

WOLFFIAN BODIES

A series of tubules that constitute the mesonephros.

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Oliver, G. Lymphatic vasculature development. Nat Rev Immunol 4, 35–45 (2004). https://doi.org/10.1038/nri1258

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