Lymphangiogenesis

[Guest guest]

You've heard of angiogenesis (growth of blood

vessels). Now meet lymphangiogenesis, the growth of

the lymphatic system

Lymphangiogenesis

(excerpts)

Studies of the last decades have revealed the

importance of angiogenesis for normal growth and for

the pathogenesis of numerous diseases. Much less

studied is lymphangiogenesis, the growth of lymphatic

vessels, which drain extravasated fluid, proteins, and

cells and transport them back to the venous

circulation.

Nonetheless, insufficient lymphangiogenesis causes

incapacitating lymphedema, while lymphatic growth

around tumors may facilitate metastatic spread of

malignant cells that ultimately kill the patient. The

recent discovery of the key lymphangiogenic factors

VEGF-C and VEGF-D and their receptor VEGFR-3 has

allowed novel insights into how the lymphatic vessels

and blood vessels coordinately grow and affect human

disease. In addition, these studies have opened novel

diagnostic and therapeutic avenues for the treatment

of lymphedema and metastasis.

When blood circulates through the vascular system,

fluid and proteins unavoidably leak out. A network of

lymphatic vessels collects the extravasated bloodless

fluid from the tissues and transfers it, as lymph, via

the collecting lymphatic vessels and thoracic duct

back into the venous circulation. Lymphatic vessels

also serve an immune function by transporting white

blood cells and antigen-presenting cells which patrol

the tissues to the various lymphoid organs, where they

elicit immune responses.

Unfortunately, malignant cells that escape from their

resident tumor can also traffic along the lymphatic

tracts to the lymph nodes and, via entry into the

circulation, cause metastatic spread to distant

organs. In view of its important functions, is not

surprising that derailed growth or function of the

lymphatic system is implicated in numerous diseases,

including lymphedema, inflammation/infection, immune

diseases, and malignancy.

The lymphatic vessels differ in many ways from the

blood vessels, but they also share many properties.

Both vascular systems are lined by an endothelium and

surrounded by a smooth muscle framework, particularly

around luminal valves in larger lymphatics (Witte et

al., 1997 ). Although both vessel types are likely to

share a common embryonic origin, they also display

several distinct molecular markers. Even certain

factors that stimulate blood vessel growth also

enhance lymphatic growth (Kubo et al., 2002 ).

Unlike blood vessels, lymphatic vessels have a

discontinuous or fenestrated basement membrane, lack

tight interendothelial junctions, and are therefore

permeable to interstitial fluid and cells (Leak, 1976

). Through specialized anchoring filaments (e.g., fine

strands of elastic fibers connecting lymphatic

endothelial cells with their surrounding pericellular

matrix [Gerli et al., 2000 ]), the lymphatic vessels

stay open when the tissue pressure rises. Compared to

the blood vessels, lymphatics are a low flow, low

pressure system and much less coagulable due to lack

of platelets and erythrocytes

Since lymphatic vessels arose from blood vessels, it

is not surprising that some of the prototype

angiogenic mechanisms are also employed in

lymphangiogenesis. This is the case for VEGF-C and

VEGF-D, which interact with VEGFR-3 in lymphatic

endothelial cells (Joukov et al., 1997 ; Kaipainen et

al., 1995 ; Achen et al., 1998 ). VEGF-C and VEGFR-3

are usually coexpressed at sites where lymphatic

vessels sprout, in the embryo (Dumont et al., 1998 ;

Kukk et al., 1996 ), and in disease (see below).

VEGF-C induces growth, migration, and survival of

primary lymphatic endothelial cells (Makinen et al.,

2001b ), stimulates lymphatic sprouting in the

chorioallantoic membrane (Oh et al., 1997 ), and, when

overexpressed in transgenic mice, lymphatic vessel

hyperplasia (Jeltsch et al., 1997 ).

Signaling via VEGFR-3 alone was sufficient for the

lymphangiogenic signals, since VEGF-CC156S, which only

activates VEGFR-3 but not VEGFR-2, induced a similar

phenotype (Veikkola et al., 2001 ). VEGF-D is also

lymphangiogenic when overexpressed in skin

keratinocytes (Veikkola et al., 2001 ). Little is

known about the expression of VEGF-D in physiological

conditions, but it is expressed in tumors (Achen et

al., 2001 ) (see below). It remains to be determined

to what extent VEGF, via binding to VEGFR-2 on

lymphatic endothelial cells (Makinen et al., 2001b ),

directly stimulates lymphangiogenesis or stimulates it

indirectly by inducing leakage and edema or other

lymphangiogenic signals.

Lymphangiogenesis appears to often accompany

angiogenesis ( Figure 3). This is understandable since

nascent blood vessels are leaky, and lack of

accompanying lymphatic growth would resulin increasing

tissue edema. For instance, during wound healing,

VEGFR-3 positive lymphatic vessels sprout from

preexisting lymphatics into the granulation tissue in

parallel with angiogenesis. Considering the complexity

of the molecular regulation of angiogenesis,

regulation of lymphangiogenesis is likely to be as

complex.

Recent experimental models have highlighted the role

of VEGF-C and VEGF-D in tumor biology. Growth of the

tumor, angiogenesis, and formation of metastases were

inhibited by anti-VEGF-D antibodies. The differences

between the tumor angiogenic properties of VEGF-C and

VEGF-D may be due to differences in their proteolytic

processing in different tumors or the variable

expression of VEGFR-2 and VEGFR-3 on blood vascular

and lymphatic endothelia.

Conclusion

The recent discovery of the key molecules VEGF-C and

VEGF-D and the isolation of lymphatic endothelial

cells have allowed studies of lymphangiogenesis at the

molecular level. Similarities between the regulation

of blood and lymphatic vessels have been observed, and

these two vessel systems appear to work in a tightly

regulated manner. Thus far, results on therapeutic

lymphangiogenesis with VEGF-C for lymphedema and

inhibition of metastatic spread of tumor cells via the

lymphatic vasculature by blocking VEGFR-3 signaling

have been most encouraging. Future clinical trials

will show the therapeutic potential of these molecules

in man.

copyright 2001 Cell Press

__________________________________________________