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

Tammela, Tuomas (author)
Zarkada, Georgia (author)
Wallgard, Elisabet (author)
Karolinska Institutet, Institutionen för medicinsk biokemi och biofysik
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Murtomäki, Aino (author)
Suchting, Steven (author)
Wirzenius, Maria (author)
Waltari, Marika (author)
Hellström, Mats (author)
Karolinska Institutet, Institutionen för medicinsk biokemi och biofysik
Schomber, Tibor (author)
Peltonen, Reetta (author)
Freitas, Catarina (author)
Duarte, Antonio (author)
Isoniemi, Helena (author)
Laakkonen, Pirjo (author)
Christofori, Gerhard (author)
Ylä-Herttuala, Seppo (author)
Shibuya, Masabumi (author)
Pytowski, Bronislaw (author)
Eichmann, Anne (author)
Betsholtz, Christer (author)
Karolinska Institutet
Alitalo, Kari (author)
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 (creator_code:org_t)
2008-06-25
2008
English.
In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 454:7204, s. 656-60
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  • Journal article (peer-reviewed)
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  • 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.

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