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.
Document Type
Article
Publication Date
10-1-2013
Digital Object Identifier (DOI)
http://dx.doi.org/10.1172/JCI67315
Repository Citation
Chavala, Sai H.; Kim, Younghee; Tudisco, Laura; Cicatiello, Valeria; Milde, Till; Kerur, Nagaraj; Claros, Nidia; Yanni, Susan; Guaiquil, Victor H.; Hauswirth, William W.; Penn, John S.; Rafii, Shahin; De Falco, Sandro; Lee, Thomas C.; and Ambati, Jayakrishna, "Retinal Angiogenesis Suppression through Small Molecule Activation of p53" (2013). Ophthalmology and Visual Science Faculty Publications. 4.
https://uknowledge.uky.edu/ophthalmology_facpub/4
Supplemental Content
Notes/Citation Information
Published in The Journal of Clinical Investigation, v. 123, no. 10, p. 4170-4181.
The copyright holder has granted permission for posting the article here.