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(1). Vascular endothelial growth factors ( VEGFs) stimulate angiogenesis and lymphangiogenesis by activating VEGF receptor ( VEGFR) tyrosine kinases in endothelial cells(2). 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(3). However, VEGFR- 3 is upregulated in the microvasculature of tumours and wounds(4,5). 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.
|Number of pages||5|
|Publication status||Published - 2008|
|MoE publication type||A1 Journal article-refereed|