Neuropilin-1 modulates p53/caspases axis to promote endothelial cell survival.
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.
Wang
Ling
L
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America.
Dutta
Shamit K
SK
Kojima
Tatsuyoshi
T
Xu
Xiaolei
X
Khosravi-Far
Roya
R
Ekker
Stephen C
SC
Mukhopadhyay
Debabrata
D
D017209:Apoptosis; D020169:Caspases / Q000378:metabolism*; D002470:Cell Survival / Q000502:physiology*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D039942:Neuropilin-1 / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000502:physiology
D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D020169:Caspases