Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation.

Abstract

Angiogenesis, the growth of new blood vessels from pre-existing vasculature, is a key process in several pathological conditions, including tumour growth and age-related macular degeneration. Vascular endothelial growth factors (VEGFs) stimulate angiogenesis and lymphangiogenesis by activating VEGF receptor (VEGFR) tyrosine kinases in endothelial cells. VEGFR-3 (also known as FLT-4) is present in all endothelia during development, and in the adult it becomes restricted to the lymphatic endothelium. However, VEGFR-3 is upregulated in the microvasculature of tumours and wounds. Here we demonstrate that VEGFR-3 is highly expressed in angiogenic sprouts, and genetic targeting of VEGFR-3 or blocking of VEGFR-3 signalling with monoclonal antibodies results in decreased sprouting, vascular density, vessel branching and endothelial cell proliferation in mouse angiogenesis models. Stimulation of VEGFR-3 augmented VEGF-induced angiogenesis and sustained angiogenesis even in the presence of VEGFR-2 (also known as KDR or FLK-1) inhibitors, whereas antibodies against VEGFR-3 and VEGFR-2 in combination resulted in additive inhibition of angiogenesis and tumour growth. Furthermore, genetic or pharmacological disruption of the Notch signalling pathway led to widespread endothelial VEGFR-3 expression and excessive sprouting, which was inhibited by blocking VEGFR-3 signals. Our results implicate VEGFR-3 as a regulator of vascular network formation. Targeting VEGFR-3 may provide additional efficacy for anti-angiogenic therapies, especially towards vessels that are resistant to VEGF or VEGFR-2 inhibitors.

• Authors: Tuomas Tammela, Georgia Zarkada, Elisabet Wallgard, Aino Murtomäki, Steven Suchting, Maria Wirzenius, Marika Waltari, Mats Hellström, Tibor Schomber, Reetta Peltonen, Catarina Freitas, Antonio Duarte, Helena Isoniemi, Pirjo Laakkonen, Gerhard Christofori, Seppo Ylä-Herttuala, Masabumi Shibuya, Bronislaw Pytowski, Anne Eichmann, Christer Betsholtz, Kari Alitalo
• Journal: Nature (Nature) Vol. 454 Issue 7204 Pg. 656-60 (Jul 31 2008) ISSN: 1476-4687 [Electronic] England
• PMID: 18594512 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Antibodies, Monoclonal
• Dipeptides
• Ligands
• N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester
• Receptors, Notch
• Vascular Endothelial Growth Factor Receptor-3

Topics

• Angiogenesis Inhibitors (pharmacology)
• Animals
• Antibodies, Monoclonal (pharmacology)
• Cell Line, Tumor
• Dipeptides (pharmacology)
• Down-Regulation
• Endothelial Cells (metabolism)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Ligands
• Mice
• Mice, Inbred BALB C
• Mice, Transgenic
• Neoplasms (blood supply, drug therapy)
• Neovascularization, Pathologic (genetics, metabolism)
• Receptors, Notch (metabolism)
• Signal Transduction
• Vascular Endothelial Growth Factor Receptor-3 (antagonists & inhibitors, metabolism)