VEGFs and receptors involved in angiogenesis versus lymphangiogenesis.
Vascular endothelial growth factors and their endothelial tyrosine kinase receptors are central regulators of vasculogenesis, angiogenesis and lymphangiogenesis. VEGF signalling through VEGFR-2 is the major angiogenic pathway, and blockage of VEGF/VEGFR-2 signalling is the first anti-angiogenic strategy for cancer therapy. VEGFR-1 seems to act as a negative regulator of VEGF-mediated angiogenesis during development, and as a stimulator of pathological angiogenesis when activated by its specific ligands PlGF and VEGF-B. PlGF recruits angiogenic macrophages to tumours, and targeting PlGF could therefore be beneficial in cancer. For VEGF-B, with very limited angiogenic potential, a new role has been identified in regulating lipid metabolism in the heart. VEGF-C and VEGF-D induce lymphangiogenesis via VEGFR-3 and have also been shown to be lymphangiogenic in tumours, stimulating metastasis. Mouse models of lymphoedema have established VEGF-C as a promising agent for pro-lymphangiogenic therapy. In addition to lymphangiogenesis, VEGFR-3 has also been shown to be important for angiogenesis, acting together with VEGF/VEGFR-2 and Dll4/Notch signalling to control angiogenic sprouting. Increasing knowledge of the mechanisms regulating (lymph)angiogenesis should enable the development of better agents to combat metastasis and the resistance of tumours towards anti-angiogenic treatment, and of pro-(lymph)angiogenic treatment methods for ischaemic diseases and lymphoedema.
Lohela
Marja
M
Molecular/Cancer Biology Laboratory, Biomedicum Helsinki and Department of Pathology, Haartman Institute, University of Helsinki, Helsinki, Finland.
Bry
Maija
M
Tammela
Tuomas
T
Alitalo
Kari
K
D042683:Angiopoietin-1 / Q000378:metabolism; D000818:Animals; D006801:Humans; D042583:Lymphangiogenesis / Q000502:physiology*; D008207:Lymphatic Metastasis; D008565:Membrane Proteins / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000502:physiology*; D020033:Protein Isoforms / Q000378:metabolism*; D042787:Receptor, TIE-2 / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D042442:Vascular Endothelial Growth Factors / Q000378:metabolism*
D042683:Angiopoietin-1; D008565:Membrane Proteins; C098069:PIGF protein, human; D020033:Protein Isoforms; D042442:Vascular Endothelial Growth Factors; D042787:Receptor, TIE-2; D040262:Receptors, Vascular Endothelial Growth Factor