Endogenous angiogenin in endothelial cells is a general requirement for cell proliferation and angiogenesis.
Angiogenin is an angiogenic protein that undergoes nuclear translocation in endothelial cells where it accumulates in the nucleolus and stimulates rRNA transcription, a rate-limiting step in ribosome biogenesis, protein translation, and cell growth. Here, we report that angiogenin is required for cell proliferation induced by various other angiogenic proteins including acidic and basic fibroblast growth factors (aFGF and bFGF), epidermal growth factor (EGF), and vascular endothelial growth factor (VEGF). Downregulation of angiogenin in endothelial cells by small interfering RNA (siRNA) and antisense results in a decrease in rRNA transcription, ribosome biogenesis, and cell proliferation induced by these angiogenic factors. Inhibitors of the nuclear translocation of angiogenin abolish the angiogenic activities of these factors. Stable angiogenin antisense transfection in HeLa cells reduces tumor angiogenesis in athymic mice despite the elevated expression level of bFGF and VEGF. Thus, nuclear angiogenin assumes an essential role in endothelial cell proliferation and is necessary for angiogenesis induced by other angiogenic factors. Angiogenin-stimulated rRNA transcription in endothelial cells may thus serve as a crossroad in the process of angiogenesis induced by various angiogenic factors.
Kishimoto
Koji
K
Department of Pathology, Harvard Medical School, 77 Avenue Louis Pasteur, NRB 930, Boston, MA 02115, USA.
Liu
Shumei
S
Tsuji
Takanori
T
Olson
Karen A
KA
Hu
Guo-Fu
GF
D043925:Angiogenesis Inducing Agents; D001483:Base Sequence; D002455:Cell Division / Q000502:physiology*; D002478:Cells, Cultured; D017931:DNA Primers; D004730:Endothelium, Vascular / Q000166:cytology; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D016376:Oligonucleotides, Antisense; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012259:Ribonuclease, Pancreatic / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D014471:Umbilical Veins
D043925:Angiogenesis Inducing Agents; D017931:DNA Primers; D016376:Oligonucleotides, Antisense; D034741:RNA, Small Interfering; C046366:angiogenin; D012259:Ribonuclease, Pancreatic