Targeted deficiency or cytosolic truncation of the VE-cadherin gene in mice impairs VEGF-mediated endothelial survival and angiogenesis.
Vascular endothelial cadherin, VE-cadherin, mediates adhesion between endothelial cells and may affect vascular morphogenesis via intracellular signaling, but the nature of these signals remains unknown. Here, targeted inactivation (VEC-/-) or truncation of the beta-catenin-binding cytosolic domain (VECdeltaC/deltaC) of the VE-cadherin gene was found not to affect assembly of endothelial cells in vascular plexi, but to impair their subsequent remodeling and maturation, causing lethality at 9.5 days of gestation. Deficiency or truncation of VE-cadherin induced endothelial apoptosis and abolished transmission of the endothelial survival signal by VEGF-A to Akt kinase and Bcl2 via reduced complex formation with VEGF receptor-2, beta-catenin, and phosphoinositide 3 (PI3)-kinase. Thus, VE-cadherin/ beta-catenin signaling controls endothelial survival.
Carmeliet
P
P
Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium. peter.carmelilet@med.kuleuven.ac.be
Lampugnani
M G
MG
Moons
L
L
Breviario
F
F
Compernolle
V
V
Bono
F
F
Balconi
G
G
Spagnuolo
R
R
Oosthuyse
B
B
Dewerchin
M
M
Zanetti
A
A
Angellilo
A
A
Mattot
V
V
Nuyens
D
D
Lutgens
E
E
Clotman
F
F
de Ruiter
M C
MC
Gittenberger-de Groot
A
A
Poelmann
R
R
Lupu
F
F
Herbert
J M
JM
Collen
D
D
Dejana
E
E
D000818:Animals; D015703:Antigens, CD; D017209:Apoptosis / Q000502:physiology; D015820:Cadherins / Q000235:genetics*; D002470:Cell Survival / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000502:physiology; D003600:Cytosol / Q000737:chemistry / Q000502:physiology; D017931:DNA Primers; D016228:Endothelial Growth Factors / Q000502:physiology*; D004730:Endothelium, Vascular / Q000737:chemistry / Q000166:cytology* / Q000648:ultrastructure; D005333:Fetus / Q000166:cytology; D018507:Gene Expression Regulation, Developmental; D006410:Hematopoiesis / Q000502:physiology; D020287:In Situ Nick-End Labeling; D007365:Intercellular Junctions / Q000502:physiology; D008222:Lymphokines / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D016297:Mutagenesis, Site-Directed; D018919:Neovascularization, Physiologic / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology; D017978:Receptors, Growth Factor / Q000502:physiology; D040262:Receptors, Vascular Endothelial Growth Factor; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D051176:beta Catenin; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D003598:Cytoskeletal Proteins; D017931:DNA Primers; D016228:Endothelial Growth Factors; D008222:Lymphokines; D019869:Phosphatidylinositol 3-Kinases; D020794:Receptor Protein-Tyrosine Kinases; D017978:Receptors, Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor; D015534:Trans-Activators; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D051176:beta Catenin; D000099152:Cadherin 5; C495267:CTNNB1 protein, mouse