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Class 3 semaphorins control vascular morphogenesis by inhibiting integrin function

Nature volume 424, pages 391–397 (2003)Cite this article

An Editorial Expression of Concern to this article was published on 21 February 2024

13 December 2022 Editor’s Note: Readers are alerted that the reliability of data presented in this manuscript is currently in question. Appropriate editorial action will be taken once this matter is resolved.

An Erratum to this article was published on 21 August 2003

This article has been updated

Abstract

The motility and morphogenesis of endothelial cells is controlled by spatio-temporally regulated activation of integrin adhesion receptors, and integrin activation is stimulated by major determinants of vascular remodelling. In order for endothelial cells to be responsive to changes in activator gradients, the adhesiveness of these cells to the extracellular matrix must be dynamic, and negative regulators of integrins could be required. Here we show that during vascular development and experimental angiogenesis, endothelial cells generate autocrine chemorepulsive signals of class 3 semaphorins (SEMA3 proteins) that localize at nascent adhesive sites in spreading endothelial cells. Disrupting endogenous SEMA3 function in endothelial cells stimulates integrin-mediated adhesion and migration to extracellular matrices, whereas exogenous SEMA3 proteins antagonize integrin activation. Misexpression of dominant negative SEMA3 receptors in chick embryo endothelial cells locks integrins in an active conformation, and severely impairs vascular remodelling. Sema3a null mice show vascular defects as well. Thus during angiogenesis endothelial SEMA3 proteins endow the vascular system with the plasticity required for its reshaping by controlling integrin function.

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Figure 1: SEMA3A expression during vascular development and experimental angiogenesis.
Figure 2: Relationships between endogenous SEMA3A and nascent focal complexes.
Figure 3: SEMA3 proteins regulate EC adhesion.
Figure 4: SEMA3 proteins regulate EC migration towards ECM.
Figure 5: SEMA3 proteins are required for chick embryonic vascular remodelling.
Figure 6: Vascular defects in Sema3a-/- mouse embryos.

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Change history

  • 13 December 2022

    Editor’s Note: Readers are alerted that the reliability of data presented in this manuscript is currently in question. Appropriate editorial action will be taken once this matter is resolved.

  • 21 February 2024

    An Editorial Expression of Concern to this paper has been published: https://doi.org/10.1038/s41586-024-07195-5

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Acknowledgements

We thank S. Hughes for RCAS-BP(A) vector and Cla12 adaptor plasmid, T. Yagi for sema3A+/- mice, T. Byzova for suggestions, FAMARCO S.p.A. and SUSA TRASPORTI S.p.A. for white Leghorn chicken eggs, M. Lobianco for administrative assistance, and L. Trusolino and M. Arese for suggestions and comments on the manuscript. This work was supported by the Associazione Italiana per la Ricerca sul Cancro, Istituto Superiore di Sanità (IV Programma Nazionale di Ricerca sull'AIDS-2001 and Progetto “Tumour therapy”), Compagnia di San Paolo, Ministero dell'Istruzione, dell'Università e della Ricerca (60%, COFIN 2002, and Progetto Strategico Oncologia), FIRB (Progetto Ingegneria dei Tessuti) (to F.B.) and the Deutsche Forschungsgemeinschaft (to A.W.P.). M.T.-L. is an Investigator of the Howard Hughes Medical Institute.

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Author notes

  1. Donatella Valdembri, Sara Zanivan, Giulia Morterra and Masahiko Taniguchi: These authors contributed equally to this work

Authors and Affiliations

  1. Division of Molecular Angiogenesis, IRCC, Institute for Cancer Research and Treatment, and Department of Oncological Sciences, University of Torino School of Medicine, 10060, Candiolo, TO, Italy

    Guido Serini, Donatella Valdembri, Sara Zanivan, Giulia Morterra, Francesca Caccavari, Luca Zammataro, Luca Primo & Federico Bussolino

  2. Division of Molecular Oncology, IRCC, Institute for Cancer Research and Treatment, and Department of Oncological Sciences, University of Torino School of Medicine, 10060, Candiolo, TO, Italy

    Luca Tamagnone

  3. Abt. Molekularbiologie Institut für Allgemeine Zoologie und Genetik, Westfälische Wilhelms-Universität, D-48149, Münster, Germany

    Constanze Burkhardt & Andreas W. Püschel

  4. Division of Developmental Biology, National Institute for Medical Research, NW7 1AA, London, UK

    Malcolm Logan

  5. Department of Biological Sciences, Howard Hughes Medical Institute, Stanford University, Stanford, California, 94305, USA

    Marc Tessier-Lavigne

  6. Department of Biochemistry and Molecular Biology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, 113-0033, Tokyo, Japan

    Masahiko Taniguchi

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Serini, G., Valdembri, D., Zanivan, S. et al. Class 3 semaphorins control vascular morphogenesis by inhibiting integrin function. Nature 424, 391–397 (2003). https://doi.org/10.1038/nature01784

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