Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation
- 25 June 2008
- journal article
- letter
- Published by Springer Science and Business Media LLC in Nature
- Vol. 454 (7204), 656-660
- https://doi.org/10.1038/nature07083
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 degeneration1. Vascular endothelial growth factors (VEGFs) stimulate angiogenesis and lymphangiogenesis by activating VEGF receptor (VEGFR) tyrosine kinases in endothelial cells2. VEGFR-3 (also known as FLT-4) is present in all endothelia during development, and in the adult it becomes restricted to the lymphatic endothelium3. However, VEGFR-3 is upregulated in the microvasculature of tumours and wounds4,5. 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.Keywords
This publication has 45 references indexed in Scilit:
- Angiogenesis in life, disease and medicineNature, 2005
- VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodiaThe Journal of cell biology, 2003
- The biology of VEGF and its receptorsNature Medicine, 2003
- Analysis of Biological Effects and Signaling Properties of Flt-1 (VEGFR-1) and KDR (VEGFR-2)Published by Elsevier BV ,2001
- Vascular Endothelial Growth Factor Receptor-3 in Lymphangiogenesis in Wound HealingThe American Journal of Pathology, 2000
- VEGFR-3 and Its Ligand VEGF-C Are Associated with Angiogenesis in Breast CancerThe American Journal of Pathology, 1999
- Heterozygous embryonic lethality induced by targeted inactivation of the VEGF geneNature, 1996
- Abnormal blood vessel development and lethality in embryos lacking a single VEGF alleleNature, 1996
- Failure of blood-island formation and vasculogenesis in Flk-1-deficient miceNature, 1995
- Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development.Proceedings of the National Academy of Sciences of the United States of America, 1995