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Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation.
Karolinska Institutet, Institutionen för medicinsk biokemi och biofysik.
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2008 (English)In: Nature, ISSN 1476-4687, Vol. 454, no 7204, 656-60 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2008. Vol. 454, no 7204, 656-60 p.
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Medical and Health Sciences
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URN: urn:nbn:se:uu:diva-159701DOI: 10.1038/nature07083PubMedID: 18594512OAI: oai:DiVA.org:uu-159701DiVA: diva2:446358
Available from: 2011-10-07 Created: 2011-10-07 Last updated: 2011-10-07

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