Class 3 semaphorins control vascular morphogenesis by inhibiting integrin function

Guido Serini; Donatella Valdembri; Sara Zanivan; Giulia Morterra; Constanze Burkhardt; Francesca Caccavari; Luca Zammataro; Luca Primo; Luca Tamagnone; Malcolm Logan; Marc Tessier-Lavigne; Masahiko Taniguchi; Andreas W Püschel; Federico Bussolino

doi:10.1038/nature01784

Class 3 semaphorins control vascular morphogenesis by inhibiting integrin function

Guido Serini, Donatella Valdembri, Sara Zanivan, Giulia Morterra, Constanze Burkhardt, Francesca Caccavari, Luca Zammataro, Luca Primo, Luca Tamagnone, Malcolm Logan, Marc Tessier-Lavigne, Masahiko Taniguchi, Andreas W Püschel, Federico Bussolino

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. [email protected]

Research output: Contribution to journal › Article › peer-review

513 Citations (Scopus)

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.

Original language	English
Pages (from-to)	391-7
Number of pages	7
Journal	Nature
Volume	424
Issue number	6947
DOIs	https://doi.org/10.1038/nature01784
Publication status	Published - 24 Jul 2003

Keywords

Animals
Autocrine Communication
Cell Adhesion
Cell Movement
Chick Embryo
Endothelium, Vascular/cytology
Extracellular Matrix/metabolism
Gene Deletion
Gene Expression Regulation
Genes, Dominant
Humans
Integrins/antagonists & inhibitors
Mice
Mice, Knockout
Morphogenesis
Neovascularization, Physiologic
Phenotype
Semaphorin-3A/genetics

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title = "Class 3 semaphorins control vascular morphogenesis by inhibiting integrin function",

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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author = "Guido Serini and Donatella Valdembri and Sara Zanivan and Giulia Morterra and Constanze Burkhardt and Francesca Caccavari and Luca Zammataro and Luca Primo and Luca Tamagnone and Malcolm Logan and Marc Tessier-Lavigne and Masahiko Taniguchi and P{\"u}schel, {Andreas W} and Federico Bussolino",

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AU - Serini, Guido

AU - Valdembri, Donatella

AU - Zanivan, Sara

AU - Morterra, Giulia

AU - Burkhardt, Constanze

AU - Caccavari, Francesca

AU - Zammataro, Luca

AU - Primo, Luca

AU - Tamagnone, Luca

AU - Logan, Malcolm

AU - Tessier-Lavigne, Marc

AU - Taniguchi, Masahiko

AU - Püschel, Andreas W

AU - Bussolino, Federico

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N2 - 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.

AB - 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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KW - Extracellular Matrix/metabolism

KW - Gene Deletion

KW - Gene Expression Regulation

KW - Genes, Dominant

KW - Humans

KW - Integrins/antagonists & inhibitors

KW - Mice

KW - Mice, Knockout

KW - Morphogenesis

KW - Neovascularization, Physiologic

KW - Phenotype

KW - Semaphorin-3A/genetics

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JO - Nature

JF - Nature

IS - 6947

ER -

Class 3 semaphorins control vascular morphogenesis by inhibiting integrin function

Abstract

Keywords

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