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VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling

Nature Cell Biology volume 13, pages 1202–1213 (2011)Cite this article

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Abstract

Angiogenesis, the growth of new blood vessels, involves specification of endothelial cells to tip cells and stalk cells, which is controlled by Notch signalling, whereas vascular endothelial growth factor receptor (VEGFR)-2 and VEGFR-3 have been implicated in angiogenic sprouting. Surprisingly, we found that endothelial deletion of Vegfr3, but not VEGFR-3-blocking antibodies, postnatally led to excessive angiogenic sprouting and branching, and decreased the level of Notch signalling, indicating that VEGFR-3 possesses passive and active signalling modalities. Furthermore, macrophages expressing the VEGFR-3 and VEGFR-2 ligand VEGF-C localized to vessel branch points, and Vegfc heterozygous mice exhibited inefficient angiogenesis characterized by decreased vascular branching. FoxC2 is a known regulator of Notch ligand and target gene expression, and Foxc2+/−;Vegfr3+/− compound heterozygosity recapitulated homozygous loss of Vegfr3. These results indicate that macrophage-derived VEGF-C activates VEGFR-3 in tip cells to reinforce Notch signalling, which contributes to the phenotypic conversion of endothelial cells at fusion points of vessel sprouts.

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Figure 1: Blood vascular hyperplasia and excessive filopodia projection in mice with a targeted deletion of Vegfr3 in the endothelium.
Figure 2: Role of VEGFR-3 tyrosine kinase activity in angiogenesis.
Figure 3: An increased level of VEGFR-2 signalling contributes to vascular hyperplasia in Vegfr3iΔEC retinas.
Figure 4: A decreased level of Notch signalling underlies excessive angiogenesis in Vegfr3iΔEC retinas.
Figure 5: Vegfc haploinsufficiency leads to instability of sprout fusion points and inefficient angiogenesis.
Figure 6: VEGF-C promotes Notch signalling in endothelial cells through VEGFR-3 and PI(3)K.
Figure 7: VEGFR-3 interacts with the transcription factor FoxC2 to control angiogenesis.

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Acknowledgements

We would like to thank T. Petrova (CePO, CHUV and University of Lausanne, Switzerland) for the Foxc2+/− mice, M. Achen and S. Stacker (Peter MacCallum Cancer Centre, Melbourne, Australia) for the Vegfd−/− mice, B. Pytowski at Eli Lilly for VEGFR-2- and VEGFR-3-blocking antibodies, M. Jeltsch (Molecular/Cancer Biology Laboratory, University of Helsinki, Finland) for generating VEGF-C antibodies, S. Kaijalainen (Molecular/Cancer Biology Laboratory, University of Helsinki, Finland) for generating mDll4-Fc and mDll4–ECTM–eGFP expression vectors, A. Alitalo (Institute of Pharmaceutical Sciences, ETH Zurich, Switzerland) for valuable help with experiments and K. Helenius for critical comments on the manuscript. The Biomedicum Molecular Imaging Unit is acknowledged for microscopy services, and N. Ihalainen, T. Laakkonen, K. Salo and T. Tainola for excellent technical assistance, as well as personnel of the Meilahti Experimental Animal Center (University of Helsinki) for expert animal husbandry. We also thank I. Rosewell (London Research Institute, UK) for generation of chimaeric mice. This work was supported by grants from the Academy of Finland, the Association for International Cancer Research, the Finnish Cancer Organizations, the Helsinki University Research Fund, the Sigrid Juselius Foundation, the Louis-Jeantet Foundation and the European Research Council (ERC-2010-AdG-268804-TX-FACTORS). T.T. was supported by personal grants from the Emil Aaltonen Foundation, the K. Albin Johansson Foundation, the Finnish Medical Foundation, the Maud Kuistila Foundation, the Orion-Farmos Research Foundation and the Paulo Foundation. G.Z. was supported by personal grants from the K. Albin Johansson Foundation, the Finnish Medical Foundation, The Paulo Foundation, the Ida Montin Foundation and the Orion-Farmos Research Foundation. H.G. was supported by Cancer Research UK, the Lister Institute of Preventive Medicine, the European Molecular Biology Organization (EMBO) Young Investigator Programme and the Leducq Transatlantic Network ARTEMIS. L.J. was supported by an EMBO long-term postdoctoral fellowship. C.A.F. was supported by a Marie Curie FP7 postdoctoral fellowship.

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Author notes

  1. Lars Jakobsson & Taija Mäkinen

    Present address: Present addresses: Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheeles Väg 2, SE171 77 Stockholm, Sweden (L.K.); Lymphatic Development Laboratory, Cancer Research UK London Research Institute, 44 Lincoln’s Inn Fields, London WC2A 3PX, UK (T.M.),

  2. Tuomas Tammela and Georgia Zarkada: These authors contributed equally to this work

Authors and Affiliations

  1. Research Programs Unit and Department of Pathology, Molecular/Cancer Biology Laboratory, Institute for Molecular Medicine Finland, Haartman Institute, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), 00014 University of Helsinki, Finland

    Tuomas Tammela, Georgia Zarkada, Harri Nurmi, Krista Heinolainen, Denis Tvorogov, Wei Zheng, Aino Murtomäki, Taija Mäkinen & Kari Alitalo

  2. Vascular Biology Laboratory, London Research Institute—Cancer Research UK, 44 Lincoln’s Inn Fields, London WC2A 3PX, UK

    Lars Jakobsson, Claudio A. Franco & Holger Gerhardt

  3. Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, New York 10461, USA

    Evelyn Aranda & Jeffrey W. Pollard

  4. Department of Biochemistry, Hamamatsu University School of Medicine, 431-3192 Hamamatsu, Japan

    Naoyuki Miura

  5. A. I. Virtanen Institute and Department of Medicine, University of Kuopio, PO Box 1627, 70211 Kuopio, Finland

    Seppo Ylä-Herttuala

  6. Institute of Ophthalmology, University College London, London EC1V 9EL, UK

    Marcus Fruttiger

  7. Institut National de la Santé et de la Recherche Médicale U833, Collège de France, 11 Place Marcelin Berthelot, 75005 Paris, France

    Anne Eichmann

  8. Vascular Patterning Laboratory, Vesalius Research Center, VIB, Campus Gasthuisberg, B-3000 Leuven, Belgium

    Holger Gerhardt

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  1. Tuomas Tammela
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Contributions

T.T. and G.Z. designed, directed and carried out experiments and data analysis, as well as interpreted results, and wrote the paper; H.N. designed and carried out cell culture and biochemistry experiments, and analysed data; L.J. carried out three-dimensional embryoid body sprouting experiments and analysed data; K.H. carried out cell culture, morphometry of retinal vessels and qRT-PCR, and analysed data; D.T. carried out biochemistry experiments and analysed data; W.Z. produced and validated Notch ligand and inhibitor proteins; C.A.F. carried out three-dimensional embryoid body sprouting experiments and analysed data; A.M. carried out retina experiments and analysed data; E.A. provided op/op retinas and carried out genotyping; N.M. generated FoxC2 antibodies; S.Y-H. generated adenoviral vectors; M.F. generated PdgfbCreERT2 mice; T.M. generated Vegfr3flox/floxmice; A.E. analysed retinas of Vegfr3+/LacZ mice; J.W.P. provided op/op retinas; H.G. directed experiments, interpreted results and helped write the paper; K.A. designed and directed experiments, interpreted results and wrote the paper.

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Correspondence to Kari Alitalo.

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K.A. is the chairman of the Scientific Advisory Board of Circadian.

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Tammela, T., Zarkada, G., Nurmi, H. et al. VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling. Nat Cell Biol 13, 1202–1213 (2011). https://doi.org/10.1038/ncb2331

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