Cell Tissue Res (2003) 314:69–84
DOI 10.1007/s00441-003-0777-2
REVIEW
Michael Jeltsch · Tuomas Tammela · Kari Alitalo ·
J
rg Wilting
Genesis and pathogenesis of lymphatic vessels
Received: 24 June 2003 / Accepted: 14 July 2003 / Published online: 27 August 2003

Springer-Verlag 2003
Abstract The lymphatic system is generally regarded as
supplementary to the blood vascular system, in that it
transports interstitial fluid, macromolecules, and immune
cells back into the blood. However, in insects, the open
hemolymphatic (or lymphohematic) system ensures the
circulation of immune cells and interstitial fluid through
the body. The Drosophila homolog of the mammalian
vascular endothelial growth factor receptor (VEGFR)
gene family is expressed in hemocytes, suggesting a close
relationship to the endothelium that develops later in
phylogeny. Lymph hearts are typical organs for the
propulsion of lymph in lower vertebrates and are still
transiently present in birds. The lymphatic endothelial
marker VEGFR-3 is transiently expressed in embryonic
blood vessels and is crucial for their development. We
therefore regard the question of whether the blood
vascular system or the lymphatic system is primary or
secondary as open. Future molecular comparisons should
be performed without any bias based on the current
prevalence of the blood vascular system over the
lymphatic system. Here, we give an overview of the
structure, function, and development of the lymphatics,
with special emphasis on the recently discovered lym-
phangiogenic growth factors.
Keywords Lymphatic endothelium · Drainage ·
Lymphedema · Lymphangiogenesis · VEGF ·
Vertebrates · Insects
Introduction
Large multi-cellular organisms with a high metabolic
demand use carrier molecules to distribute oxygen within
their body. In vertebrates, a closed vascular system guides
the transport of these molecules. Therefore, the vascular
system has to be functional early in development. When
the human embryo reaches the size of approximately
3 mm at embryonic day 22, its heart starts beating. Later,
when the cardiovascular system is functioning, the
lymphatic system develops, forming a second vascular
system. Unlike the cardiovascular system, it is not a
circulatory system. Lymphatic flow starts in blind-ended
capillary networks that penetrate most of the body tissues
(Figs. 1, 2). Collecting lymphatics drain the capillary
networks, and after collecting fluid from many tributaries,
the largest collecting lymphatic vessels (the thoracic duct
and the right lymphatic duct) ultimately reach the veins.
Compared with our tremendous knowledge about the
cardiovascular system, presumably our understanding of
the lymphatic system is still rudimentary. The discovery
and exploration of the lymphatic system have lagged
behind those of the cardiovascular system, because of the
immediately obvious importance of the cardiovascular
system.
Retrospectively, three heydays have shaped our un-
derstanding of the lymphatic system. The first took place
during the first years of the 20th century when researchers
such as Sabin, Kampmeier, Huntington, and McClure
were studying the ontogeny of the lymphatic system (for a
review, see Wilting et al. 1999). The second boost of
knowledge resulted from the use of the electron micro-
scope during the 1960s to solve questions about the fine
structure of the initial lymphatics and their function (for a
review, see Leak 1970). At the moment, lymphatic
research is experiencing an impressive comeback thanks
to molecular biology, to genetics, and last but not least, to
the discovery of markers specific for the lymphatic
endothelium (for a review, see Oliver and Detmar 2002).
M. Jeltsch · T. Tammela · K. Alitalo (
)
)
Molecular and Cancer Biology Laboratory,
Ludwig Institute for Cancer Research,
and Helsinki University Central Hospital,
Biomedicum Helsinki,
University of Helsinki,
Haartmaninkatu 8, Postbox 63, 00014 Helsinki, Finland
e-mail: Kari.alitalo@helsinki.fi
Tel.: +358-9-19125511
Fax: +358-9-19125510
J. Wilting
Children’s Hospital,
Robert-Koch-Strasse 40, 37075 Gttingen, Germany

Cardiovascular system
During early embryogenesis, most of the blood vessels
form by vasculogenesis, the in situ formation of an
immature network of endothelial channels by the differ-
entiation of precursor cells (angioblasts). Vasculogenesis
starts in extra-embryonic tissues where putative meso-
dermal precursor cells (hemangioblasts) aggregate into
blood islands. Cells in the center of a blood island develop
into hematopoietic cells, and those at the periphery
differentiate into angioblasts. In the embryo, vasculogen-
esis gives rise to the heart endocardium, the paired dorsal
aortas, and the primary vasculature of endoderm-derived
organs (e.g. lung, liver, and pancreas; for a review, see
Wilting and Christ 1996). The primary vascular network
grows and is remodeled into a functional hierarchical
system containing large caliber conduit vessels and small
capillaries for diffusion. Various cellular mechanisms
(splitting, fusion, sprouting, and intercalation) participate
in this remodeling and expansion, a process collectively
referred to as angiogenesis (for a review, see Risau 1998).
Whereas most organs become vascularized by a combi-
nation of vasculogenesis and angiogenesis, avascular
ectodermal tissues, such as the brain, initially become
vascularized exclusively by angiogenic mechanisms
(Plate 1999). The endothelial cell layer becomes invested
with mesodermal cells: a covering of pericytes, muscular
tissue, and connective tissue. Therefore, vessel formation
also requires the recruitment and organization of non-
endothelial cells (for a review, see Carmeliet 2000).
Angiogenesis has been assumed to be the only means of
neovascularization in adult organisms, but recently, a
population of progenitor cells able to differentiate into
endothelial cells has been isolated from the circulating
blood of adults and identified as originating from the bone
marrow (Asahara et al. 1997, 1999; Shi et al. 1998;
Crosby et al. 2000; for a review, see Rafii and Lyden
2003). However, the relative contribution of circulating
precursors to physiological or pathological angiogenesis
needs to be determined. Only a few physiological
processes in the adult involve endothelial cell prolifera-
tion, e.g., the female reproductive cycle (for a review, see
Fig. 1 Schematic view of the
lymphatic system
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