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
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
3. Abt. Molekularbiologie Institut für Allgemeine Zoologie und Genetik, Westfälische Wilhelms-Universität, D-48149 Münster, Germany
4. Division of Developmental Biology, National Institute for Medical Research, London NW7 1AA, UK
5. Department of Biological Sciences, Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA
6. Department of Biochemistry and Molecular Biology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
7. These authors contributed equally to this work

Correspondence to: Guido Serini¹Federico Bussolino¹ Correspondence and requests for materials should be addressed to G.S. (Email: guido.serini@ircc.it) or F.B. (Email: federico.bussolino@ircc.it).

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.