Neuron-derived neurotrophic factor functions as a novel modulator that enhances endothelial cell function and revascularization processes.
Strategies to stimulate revascularization are valuable for cardiovascular diseases. Here we identify neuron-derived neurotrophic factor (NDNF)/epidermacan as a secreted molecule that is up-regulated in endothelial cells in ischemic limbs of mice. NDNF was secreted from cultured human endothelial cells, and its secretion was stimulated by hypoxia. NDNF promoted endothelial cell network formation and survival in vitro through activation of Akt/endothelial NOS (eNOS) signaling involving integrin αvβ3. Conversely, siRNA-mediated knockdown of NDNF in endothelial cells led to reduction of cellular responses and basal Akt signaling. Intramuscular overexpression of NDNF led to enhanced blood flow recovery and capillary density in ischemic limbs of mice, which was accompanied by enhanced phosphorylation of Akt and eNOS. The stimulatory actions of NDNF on perfusion recovery in ischemic muscles of mice were abolished by eNOS deficiency or NOS inhibition. Furthermore, siRNA-mediated reduction of NDNF in muscles of mice resulted in reduction of perfusion recovery and phosphorylation of Akt and eNOS in response to ischemia. Our data indicate that NDNF acts as an endogenous modulator that promotes endothelial cell function and ischemia-induced revascularization through eNOS-dependent mechanisms. Thus, NDNF can represent a therapeutic target for the manipulation of ischemic vascular disorders.
From the Department of Molecular Cardiology and.
Koji
K
Ohashi
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
Takashi
T
Enomoto
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
Yusuke
Y
Joki
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
Rei
R
Shibata
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
Yasuhiro
Y
Ogura
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
Yoshiyuki
Y
Kataoka
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
Yuuki
Y
Shimizu
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
Takahiro
T
Kambara
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
Yusuke
Y
Uemura
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
Daisuke
D
Yuasa
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
Kazuhiro
K
Matsuo
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
Satoko
S
Hayakawa
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
Mizuho
M
Hiramatsu-Ito
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
Toyoaki
T
Murohara
From the Department of Molecular Cardiology and nouchi@med.nagoya-u.ac.jp.
Noriyuki
N
Ouchi
D000818:Animals; D001775:Blood Circulation; D001808:Blood Vessels / Q000166:cytology / Q000473:pathology / Q000502:physiology / Q000503:physiopathology; D019556:COS Cells; D002470:Cell Survival; D002522:Chlorocebus aethiops; D042783:Endothelial Cells / Q000166:cytology* / Q000473:pathology; D006801:Humans; D007511:Ischemia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
C561304:NDNF protein, mouse; D009414:Nerve Growth Factors; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt
Akt; Angiogenesis; Apoptosis; Endothelial Cell; Ischemia; Neuron-derived Neurotrophic Factor; Nitric Oxide Synthase