title: Retinal angiogenesis suppression through small molecule activation of p53.
abstract: Neovascular age-related macular degeneration is a leading cause of irreversible vision loss in the Western world. Cytokine-targeted therapies (such as anti-vascular endothelial growth factor) are effective in treating pathologic ocular angiogenesis, but have not led to a durable effect and often require indefinite treatment. Here, we show that Nutlin-3, a small molecule antagonist of the E3 ubiquitin protein ligase MDM2, inhibited angiogenesis in several model systems. We found that a functional p53 pathway was essential for Nutlin-3-mediated retinal antiangiogenesis and disruption of the p53 transcriptional network abolished the antiangiogenic activity of Nutlin-3. Nutlin-3 did not inhibit established, mature blood vessels in the adult mouse retina, suggesting that only proliferating retinal vessels are sensitive to Nutlin-3. Furthermore, Nutlin-3 inhibited angiogenesis in nonretinal models such as the hind limb ischemia model. Our work demonstrates that Nutlin-3 functions through an antiproliferative pathway with conceivable advantages over existing cytokine-targeted antiangiogenesis therapies.
authors.forename: Sai H
authors.initials: SH
authors.lastname: Chavala
authors.forename: Younghee
authors.initials: Y
authors.lastname: Kim
authors.forename: Laura
authors.initials: L
authors.lastname: Tudisco
authors.forename: Valeria
authors.initials: V
authors.lastname: Cicatiello
authors.forename: Till
authors.initials: T
authors.lastname: Milde
authors.forename: Nagaraj
authors.initials: N
authors.lastname: Kerur
authors.forename: Nidia
authors.initials: N
authors.lastname: Claros
authors.forename: Susan
authors.initials: S
authors.lastname: Yanni
authors.forename: Victor H
authors.initials: VH
authors.lastname: Guaiquil
authors.forename: William W
authors.initials: WW
authors.lastname: Hauswirth
authors.forename: John S
authors.initials: JS
authors.lastname: Penn
authors.forename: Shahin
authors.initials: S
authors.lastname: Rafii
authors.forename: Sandro
authors.initials: S
authors.lastname: De Falco
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Lee
authors.forename: Jayakrishna
authors.initials: J
authors.lastname: Ambati
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D006614:Hindlimb / Q000098:blood supply; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007511:Ischemia / Q000188:drug therapy; D008268:Macular Degeneration / Q000188:drug therapy; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D012171:Retinal Vessels / Q000187:drug effects / Q000502:physiology*; D015533:Transcriptional Activation / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; D007093:Imidazoles; D010879:Piperazines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3
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