PTEN mediates Notch-dependent stalk cell arrest in angiogenesis

Coordinated activity of VEGF and Notch signals guides the endothelial cell (EC) specification into tip and stalk cells during angiogenesis. Notch activation in stalk cells leads to proliferation arrest via an unknown mechanism. By using gain- and loss-of-function gene-targeting approaches, here we s...

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Detalles Bibliográficos
Autores: Serra, Helena, Chivite, Iñigo, Angulo-Urarte, Ana, Soler, Adriana, Sutherland, James D, Arruabarrena-Aristorena, Amaia, Ragab, Anan, Lim, Radiance, Malumbres Martinez, Marcos, Fruttiger, Marcus, Potente, Michael, Serrano Marugan, Manuel, Fabra, Àngels, Viñals, Francesc, Casanovas, Oriol, Pandolfi, Pier Paolo, Bigas, Anna, Carracedo, Arkaitz, Gerhardt, Holger, Graupera, Mariona
Tipo de recurso: artículo
Fecha de publicación:2015
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/10008
Acceso en línea:http://hdl.handle.net/20.500.12105/10008
Access Level:acceso abierto
Palabra clave:Anaphase-Promoting Complex-Cyclosome
Animals
Cdh1 Proteins
Cell Proliferation
Endothelial Cells
Fluorescent Antibody Technique
Immunoblotting
Mice
Neovascularization, Physiologic
PTEN Phosphohydrolase
Polymerase Chain Reaction
RNA, Messenger
Receptors, Notch
Descripción
Sumario:Coordinated activity of VEGF and Notch signals guides the endothelial cell (EC) specification into tip and stalk cells during angiogenesis. Notch activation in stalk cells leads to proliferation arrest via an unknown mechanism. By using gain- and loss-of-function gene-targeting approaches, here we show that PTEN is crucial for blocking stalk cell proliferation downstream of Notch, and this is critical for mouse vessel development. Endothelial deletion of PTEN results in vascular hyperplasia due to a failure to mediate Notch-induced proliferation arrest. Conversely, overexpression of PTEN reduces vascular density and abrogates the increase in EC proliferation induced by Notch blockade. PTEN is a lipid/protein phosphatase that also has nuclear phosphatase-independent functions. We show that both the catalytic and non-catalytic APC/C-Fzr1/Cdh1-mediated activities of PTEN are required for stalk cells' proliferative arrest. These findings define a Notch-PTEN signalling axis as an orchestrator of vessel density and implicate the PTEN-APC/C-Fzr1/Cdh1 hub in angiogenesis.

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