A novel nucleic acid analogue shows strong angiogenic activity.
A novel nucleic acid analogue (2Cl-C.OXT-A) significantly stimulated tube formation of human umbilical endothelial cells (HUVEC). Its maximum potency at 100muM was stronger than that of vascular endothelial growth factor (VEGF), a positive control. At this concentration, 2Cl-C.OXT-A moderately stimulated proliferation as well as migration of HUVEC. To gain mechanistic insights how 2Cl-C.OXT-A promotes angiogenic responses in HUVEC, we performed immunoblot analyses using phospho-specific antibodies as probes. 2Cl-C.OXT-A induced robust phosphorylation/activation of MAP kinase ERK1/2 and an upstream MAP kinase kinase MEK. Conversely, a MEK inhibitor PD98059 abolished ERK1/2 activation and tube formation both enhanced by 2Cl-C.OXT-A. In contrast, MAP kinase responses elicited by 2Cl-C.OXT-A were not inhibited by SU5416, a specific inhibitor of VEGF receptor tyrosine kinase. Collectively these results suggest that 2Cl-C.OXT-A-induces angiogenic responses in HUVEC mediated by a MAP kinase cascade comprising MEK and ERK1/2, but independently of VEGF receptor tyrosine kinase. In vivo assay using chicken chorioallantoic membrane (CAM) and rabbit cornea also suggested the angiogenic potency of 2Cl-C.OXT-A.
Tsukamoto
Ikuko
I
Department of Pharmaco-Bio-Informatics, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa 761-0793, Japan. tukamoto@med.kagawa-u.ac.jp
Sakakibara
Norikazu
N
Maruyama
Tokumi
T
Igarashi
Junsuke
J
Kosaka
Hiroaki
H
Kubota
Yasuo
Y
Tokuda
Masaaki
M
Ashino
Hiromi
H
Hattori
Kenichi
K
Tanaka
Shinji
S
Kawata
Mitsuhiro
M
Konishi
Ryoji
R
D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D043925:Angiogenesis Inducing Agents / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009696:Nucleic Acids / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits
C552550:2Cl-C.OXT-A; D043925:Angiogenesis Inducing Agents; D009696:Nucleic Acids; D000241:Adenosine