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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 4

Nutlin-3 induces apoptosis in HUVECs but not in HUVSMCs.

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Nutlin-3 induces apoptosis in HUVECs but not in HUVSMCs.
(A) Representat...
(A) Representative HUVEC flow cytometry plots from 3 independent experiments were run in duplicate for 8 hours. (B) TUNEL staining images of HUVECs. Original magnification, ×200. (C) The ratio of the number of TUNEL-positive cells to the number of nuclei found in 5 random fields from each condition are counted by 2 masked observers. Data are mean ± SD and represent 2 independent experiments. (D) qRT-PCR of HUVECs treated for 4 hours. Relative BAX and BCL-2 expression are presented as a ratio. Values are provided as a percentage of DMSO (control) and expressed as mean ± SD. (n = 9 from 3 independent experiments).*P < 0.05. (E) Representative HUVEC flow cytometry plots from 3 independent experiments were run in duplicate for 36 hours. (F) qRT-PCR of BAX and BCL-2 expression in HUVSMCs treated for 4 hours. Values are provided given as a percentage of DMSO (control) ± SD. (n = 12 from 4 independent experiments) NS, P > 0.05. Amount of Nutlin-3A and Nutlin-3B was 7.5 μM and that of Etoposide was 10 μM.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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