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One of the leading causes of vision loss is age-related macular degeneration associated with formation of new retinal blood vessels. Current treatments for this condition involve use of antibodies against VEGF, which is known to stimulate angiogenesis. This therapy requires frequent treatment and many patients are unresponsive. Sai Chavala and colleagues at the University of North Carolina examined the potential of the small molecule Nutlin-3 as an inhibitor of retinal angiogenesis. The authors found that Nutlin-3 inhibited new blood vessel formation in several model systems without affecting mature blood vessels. The action of Nutlin-3 was through disruption of the p53 transcriptional network and was also effective in preventing angiogenesis in a nonocular angiogenesis model. The above confocal image is of a paraffin embedded section of the retinal vasculature from an adult mouse 5 days after injection of Nutlin-3. The vasculature (green) is recognized by the lectin GS-IB4.
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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
Sai H. Chavala, Younghee Kim, Laura Tudisco, Valeria Cicatiello, Till Milde, Nagaraj Kerur, Nidia Claros, Susan Yanni, Victor H. Guaiquil, William W. Hauswirth, John S. Penn, Shahin Rafii, Sandro De Falco, Thomas C. Lee, Jayakrishna Ambati
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