HIF-1α and HIF-2α redundantly promote retinal neovascularization in patients with ischemic retinal disease
Jing Zhang, Yaowu Qin, Mireya Martinez, Miguel Flores-Bellver, Murilo Rodrigues, Aumreetam Dinabandhu, Xuan Cao, Monika Deshpande, Yu Qin, Silvia Aparicio-Domingo, Yuan Rui, Stephany Y. Tzeng, Shaima Salman, Jin Yuan, Adrienne W. Scott, Jordan J. Green, M. Valeria Canto-Soler, Gregg L. Semenza, Silvia Montaner, Akrit Sodhi
Jing Zhang, Yaowu Qin, Mireya Martinez, Miguel Flores-Bellver, Murilo Rodrigues, Aumreetam Dinabandhu, Xuan Cao, Monika Deshpande, Yu Qin, Silvia Aparicio-Domingo, Yuan Rui, Stephany Y. Tzeng, Shaima Salman, Jin Yuan, Adrienne W. Scott, Jordan J. Green, M. Valeria Canto-Soler, Gregg L. Semenza, Silvia Montaner, Akrit Sodhi
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Research Article Angiogenesis Ophthalmology

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

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.

Authors

Jing Zhang, Yaowu Qin, Mireya Martinez, Miguel Flores-Bellver, Murilo Rodrigues, Aumreetam Dinabandhu, Xuan Cao, Monika Deshpande, Yu Qin, Silvia Aparicio-Domingo, Yuan Rui, Stephany Y. Tzeng, Shaima Salman, Jin Yuan, Adrienne W. Scott, Jordan J. Green, M. Valeria Canto-Soler, Gregg L. Semenza, Silvia Montaner, Akrit Sodhi

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Figure 6

HIF-1α accumulation is necessary to promote ANGPTL4 and VEGF expression in retinal Müller cells.

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HIF-1α accumulation is necessary to promote ANGPTL4 and VEGF expression ...
(A and B) Accumulation of HIF-1α and HIF-2α in MIO-M1 cells cultured in hypoxia by WB (A) and IF (B). (C) Expression of HIF-1α and HIF-2α by WB in MIO-M1 cells exposed to hypoxia after knockdown of HIF-1α, HIF-2α, or both, by RNAi. (D and E) ANGPTL4 (D) and VEGF (E) mRNA expression in response to RNAi targeting HIF-1α, HIF-2α, or both, in MIO-M1 cells exposed to hypoxia. (F) VEGF protein expression in response to RNAi targeting HIF-1α, HIF-2α, or both, in MIO-M1 cells exposed to hypoxia. Data are shown as mean ± SD. Statistical analyses were performed 2-way ANOVA with Bonferroni’s multiple-comparison test (D–F). h, hours; NS, nonsignificant. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.