Inhibition of angiogenesis and vascular leakiness by angiopoietin-related protein 4.
Angiopoietins and angiopoietin-related proteins (ARPs) have been shown to regulate angiogenesis, a process essential for various neovascular diseases including tumors. Here, we identify ARP4/fasting-induced adipose factor/peroxisome proliferator-activated receptor gamma angiopoietin-related as a novel antiangiogenic modulatory factor. We hypothesized that ARP4 may regulate angiogenesis. In vitro experiments using purified recombinant ARP4 protein revealed that ARP4 markedly inhibited the proliferation, chemotaxis, and tubule formation of endothelial cells. Moreover, using corneal neovascularization and Miles permeability assays, we found that both vascular endothelial growth factor-induced in vivo angiogenesis and vascular leakiness were significantly inhibited by the addition of ARP4. Finally, we found remarkable suppression of tumor growth within the dermal layer associated with decreased numbers of invading blood vessels in transgenic mice that express ARP4 in the skin driven by the keratinocyte promoter. These findings demonstrate that ARP4 functions as a novel antiangiogenic modulatory factor and indicate a potential therapeutic effect of ARP4 in neoplastic diseases.
Ito
Yasuhiro
Y
Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, Tokyo 160-8582, Japan.
Oike
Yuichi
Y
Yasunaga
Kunio
K
Hamada
Koichi
K
Miyata
Keishi
K
Matsumoto
Shun-Ichiro
S
Sugano
Sumio
S
Tanihara
Hidenobu
H
Masuho
Yasuhiko
Y
Suda
Toshio
T
D020533:Angiogenesis Inhibitors / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D003315:Cornea / Q000098:blood supply; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008870:Microtubules / Q000187:drug effects; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011994:Recombinant Proteins / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000502:physiology
C474772:ANGPTL4 protein, human; D020533:Angiogenesis Inhibitors; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; D036341:Intercellular Signaling Peptides and Proteins; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A