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Retinal angiogenesis suppression through small molecule activation of p53
Sai H. Chavala, … , Thomas C. Lee, Jayakrishna Ambati
Sai H. Chavala, … , Thomas C. Lee, Jayakrishna Ambati
Published September 9, 2013
Citation Information: J Clin Invest. 2013;123(10):4170-4181. https://doi.org/10.1172/JCI67315.
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Research Article Vascular biology

Retinal angiogenesis suppression through small molecule activation of p53

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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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Figure 1

Nutlin-3 inhibits HUVEC proliferation.

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Nutlin-3 inhibits HUVEC proliferation.
(A) Nutlin-3A or Nutlin-3B in 1, ...
(A) Nutlin-3A or Nutlin-3B in 1, 5, or 10 μM concentrations was added to proliferating HUVECs for 36 hours. HUVECs were either unchallenged or challenged with VEGF-A or FGF-2 during the incubation. (B) Cell viability was measured at 12, 24, and 36 hours after incubation. (C) Phase contrast images of representative conditions of serum free, unchallenged HUVECs at 36 hours. Original magnification, ×100.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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