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Interactions of VEGF ligands and VEGFRs

interactions of VEGF ligands

VEGF ligands, shown in purple boxes, bind to their associated receptors, leading to receptor dimerisation and subsequent signal transduction. For example, two VEGFR-2 receptors with bound VEGF ligands would dimerise and be activated, causing phosphorylation of the receptor TK domains and a subsequent cellular signalling cascade that leads to angiogenesis. Of the primary receptors, VEGFR-2 is thought to mediate the majority of the angiogenic effects of VEGF.3,4

Hicklin DJ, Ellis LM. J Clin Oncol 2005;23:1011–27. Reprinted with permission from the American Society of Clinical Oncology.

VEGFRs

VEGF ligands mediate their angiogenic effects by binding to specific VEGFRs, leading to receptor dimerisation and subsequent signal transduction. VEGF ligands bind to three primary receptors and two co-receptors. Of the primary receptors, VEGFR-1 and VEGFR-2 are mainly associated with angiogenesis. The third primary receptor, VEGFR-3, is associated with lymphangiogenesis.3,4

 

Endothelial expression of VEGFRs varies among the three primary receptors; VEGFR-2 is expressed on almost all endothelial cells, whereas VEGFR-1 and -3 are selectively expressed in distinct vascular beds.4 The neuropilin-1 (NP-1 or NRP-1) and NP-2 (or NRP-2) receptors are thought to increase the binding affinity of the various VEGF ligands to these primary receptors, although the specific roles of NP-1 and NP-2 in angiogenesis are not known.3,4,45

 

While VEGFRs are well known to be present on the surface of endothelial cells, recent research suggests that they may also be expressed by tumour cells.4,46,47 The significance of this finding requires further investigation.

 

To learn more about each member of the VEGF family of receptors, click on the links in the table below.

  

Receptor

Activity

Ligands

VEGFR-1

Stimulates developmental (embryogenic) angiogenesis

VEGF-A (VEGF)
VEGF-B
PlGF

VEGFR-2

Mediates most downstream angiogenic effects of VEGF

VEGF
VEGF-C
VEGF-D
VEGF-E

VEGFR-3

Promotes lymphangiogenesis

VEGF-C
VEGF-D
   
VEGFR-1

VEGFR-1 (Flt-1)

VEGFR-1, a key receptor during embryogenesis, does not appear to be critical to tumour angiogenesis.4

Hicklin DJ, Ellis LM. J Clin Oncol 2005;23:1011–27. Reprinted with permission from the American Society of Clinical Oncology.

VEGFR-1

VEGFR-1 can not only bind VEGF, but also VEGF-B and PlGF. VEGFR-1 is a key receptor in developmental angiogenesis (i.e. vessel formation during embryogenesis), but does not appear to be critical to pathogenic angiogenesis. Its role appears to vary with stages of development, physiological and pathophysiological conditions and cell type.4,48

 
VEGFR-2

VEGFR-2 (Flk-1/KDR)

The majority of downstream angiogenic effects of VEGF including endothelial cell proliferation, invasion, and migration, are mediated by VEGFR-2.4,49

Rini BI, Small EJ. J Clin Oncol 2005;23:1028–43. Reprinted with permission from the American Society of Clinical Oncology.

VEGFR-2

VEGFR-2 mediates the majority of the downstream angiogenic effects of VEGF, including4

 
  • Microvascular permeability
  • Endothelial cell proliferation
  • Invasion
  • Migration
  • Survival.
 

Recent work suggests that VEGFR-2 can be activated selectively by VEGF-E to stimulate angiogenesis on its own.50 The activation and signalling of VEGFR-2 may be positively or negatively influenced by co-expression and activation of VEGFR-1.4

VEGFR-3

VEGFR-3 (Flt-4)

VEGFR-3 is found only in lymphatic endothelial cells in adults, and may be involved in the development of lymph node metastases.4,51–54

Hicklin DJ, Ellis LM. J Clin Oncol 2005;23:1011–27. Reprinted with permission from the American Society of Clinical Oncology.

VEGFR-3

VEGFR-3 promotes lymphangiogenesis and is found only in lymphatic endothelial cells in adults.4 There is also evidence that VEGFR-3 plays a role in maintaining vascular integrity by modulating VEGFR-2 activity.

 

VEGFR-3 activation has been observed in several solid tumour types, including melanoma and breast cancer. In these tumours, elevated levels of VEGFR-3 ligands VEGF-C and VEGF-D are associated with lymph node metastases.42–54