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    HIF-1α and HIF-2α redundantly promote retinal neovascularization in patients with ischemic retinal disease

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    Author
    Zhang, Jing
    Qin, Yaowu
    Martinez, Mireya
    Flores-Bellver, Miguel
    Rodrigues, Murilo
    Dinabandhu, Aumreetam
    Cao, Xuan
    Deshpande, Monika
    Qin, Yu
    Aparicio-Domingo, Silvia
    Rui, Yuan
    Tzeng, Stephany Y
    Salman, Shaima
    Yuan, Jin
    Scott, Adrienne W
    Green, Jordan J
    Canto-Soler, M Valeria
    Semenza, Gregg L
    Montaner, Silvia
    Sodhi, Akrit
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    Date
    2021-06-15
    Journal
    Journal of Clinical Investigation
    Publisher
    American Society for Clinical Investigation
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1172/JCI139202
    Abstract
    Therapies targeting VEGF have proven only modestly effective for the treatment of proliferative sickle cell retinopathy (PSR), the leading cause of blindness in patients with sickle cell disease. Here, we shift our attention upstream from the genes that promote retinal neovascularization (NV) to the transcription factors that regulate their expression. We demonstrated increased expression of HIF-1α and HIF-2α in the ischemic inner retina of PSR eyes. Although both HIFs participated in promoting VEGF expression by hypoxic retinal Müller cells, HIF-1 alone was sufficient to promote retinal NV in mice, suggesting that therapies targeting only HIF-2 would not be adequate to prevent PSR. Nonetheless, administration of a HIF-2-specific inhibitor currently in clinical trials (PT2385) inhibited NV in the oxygen-induced retinopathy (OIR) mouse model. To unravel these discordant observations, we examined the expression of HIFs in OIR mice and demonstrated rapid but transient accumulation of HIF-1α but delayed and sustained accumulation of HIF-2α; simultaneous expression of HIF-1α and HIF-2α was not observed. Staggered HIF expression was corroborated in hypoxic adult mouse retinal explants but not in human retinal organoids, suggesting that this phenomenon may be unique to mice. Using pharmacological inhibition or an in vivo nanoparticle-mediated RNAi approach, we demonstrated that inhibiting either HIF was effective for preventing NV in OIR mice. Collectively, these results explain why inhibition of either HIF-1α or HIF-2α is equally effective for preventing retinal NV in mice but suggest that therapies targeting both HIFs will be necessary to prevent NV in patients with PSR.
    Keyword
    Angiogenesis
    Hypoxia
    Mouse models
    Ophthalmology
    Retinopathy
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/16037
    ae974a485f413a2113503eed53cd6c53
    10.1172/JCI139202
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