HIF-1α and HIF-2α redundantly promote retinal neovascularization in patients with ischemic retinal disease
Author
Zhang, JingQin, 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
Date
2021-06-15Journal
Journal of Clinical InvestigationPublisher
American Society for Clinical InvestigationType
Article
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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.Identifier to cite or link to this item
http://hdl.handle.net/10713/16037ae974a485f413a2113503eed53cd6c53
10.1172/JCI139202
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