1. Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki and the Haartman Institute University of Helsinki, PO Box 63 (Haartmaninkatu 8), 00014 Helsinki, Finland
2. Division of Matrix Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 77 Stockholm, Sweden
3. Institut National de la Santé et de la Recherche Médicale U833, Collège de France, 11 Place Marcelin Berthelot, 75005 Paris, France
4. Center of Biomedicine, Department of Clinical-Biological Sciences, University of Basel, Mattenstrasse 28, CH-4058 Basel, Switzerland
5. Department of Transplantation and Hepatic Surgery, Helsinki University Central Hospital, PO Box 263, 00029 Helsinki, Finland
6. The Interdisciplinary Centre of Research in Animal Health (CIISA), Faculty of Veterinary Medicine, Technical University of Lisbon, 1300-474 Lisbon, Portugal
7. A. I. Virtanen Institute and Department of Medicine, University of Kuopio, PO Box 1627, 70211 Kuopio, Finland
8. Department of Molecular Oncology, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8519, Japan
9. ImClone Systems, 180 Varick Street, New York 10014, USA
10. These authors contributed equally to this work.

Correspondence to: Kari Alitalo¹ Correspondence and requests for materials should be addressed to K.A. (Email: kari.alitalo@helsinki.fi).

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 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.

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