Class 3 semaphorins control vascular morphogenesis by inhibiting integrin function.
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.
Serini
Guido
G
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@ircc.it
Valdembri
Donatella
D
Zanivan
Sara
S
Morterra
Giulia
G
Burkhardt
Constanze
C
Caccavari
Francesca
F
Zammataro
Luca
L
Primo
Luca
L
Tamagnone
Luca
L
Logan
Malcolm
M
Tessier-Lavigne
Marc
M
Taniguchi
Masahiko
M
Püschel
Andreas W
AW
Bussolino
Federico
F
D000818:Animals; D019898:Autocrine Communication; D002448:Cell Adhesion; D002465:Cell Movement; D002642:Chick Embryo; D004730:Endothelium, Vascular / Q000166:cytology* / Q000196:embryology / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D006801:Humans; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis; D018919:Neovascularization, Physiologic; D010641:Phenotype; D040121:Semaphorin-3A / Q000235:genetics / Q000378:metabolism*
D016023:Integrins; D040121:Semaphorin-3A