Neuropilin-1 modulates p53/caspases axis to promote endothelial cell survival

• Published in: PloS one 2007-11, Vol.2 (11), p.e1161-e1161
• Main Authors: Wang, Ling, Dutta, Shamit K, Kojima, Tatsuyoshi, Xu, Xiaolei, Khosravi-Far, Roya, Ekker, Stephen C, Mukhopadhyay, Debabrata
• Format: Article
• Language: English
• Subjects: Activation; AKT protein; Amino acids; Analysis; Angiogenesis; Apoptosis; Biochemistry; Breast cancer; Caspases - metabolism; Cell Biology/Cell Signaling; Cell culture; Cell survival; Cell Survival - physiology; Cells, Cultured; Danio rerio; Deactivation; Development and progression; DNA damage; Endothelial cells; Endothelium; Endothelium, Vascular - cytology; Endothelium, Vascular - metabolism; Humans; Hypoxia; Identification; Inactivation; Kinases; Ligands; Medicine; Molecular biology; Molecular modelling; Neuropilin; Neuropilin-1 - physiology; p53 Protein; Permeability; Proteins; Rodents; Signal transduction; Signaling; Stem cells; Survival; Transcription factors; Tumor proteins; Tumor Suppressor Protein p53 - physiology; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - physiology; Vascular Endothelial Growth Factor Receptor-2 - physiology; Vascular endothelial growth factor receptors; Vascular permeability factor; Zebrafish
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0001161

Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF), one of the crucial pro-angiogenic factors, functions as a potent inhibitor of endothelial cell (EC) apoptosis. Previous progress has been made towards delineating the VPF/VEGF survival signaling downstream of the activation of VEGFR-2. Here, we seek to define the function of NRP-1 in VPF/VEGF-induced survival signaling in EC and to elucidate the concomitant molecular signaling events that are pivotal for our understanding of the signaling of VPF/VEGF. Utilizing two different in vitro cell culture systems and an in vivo zebrafish model, we demonstrate that NRP-1 mediates VPF/VEGF-induced EC survival independent of VEGFR-2. Furthermore, we show here a novel mechanism for NRP-1-specific control of the anti-apoptotic pathway in EC through involvement of the NRP-1-interacting protein (NIP/GIPC) in the activation of PI-3K/Akt and subsequent inactivation of p53 pathways and FoxOs, as well as activation of p21. This study, by elucidating the mechanisms that govern VPF/VEGF-induced EC survival signaling via NRP-1, contributes to a better understanding of molecular mechanisms of cardiovascular development and disease and widens the possibilities for better therapeutic targets.