HIF-1α and HIF-2α redundantly promote retinal neovascularization in patients with ischemic retinal disease
Tzeng, Stephany Y
Scott, Adrienne W
Green, Jordan J
Canto-Soler, M Valeria
Semenza, Gregg L
JournalJournal of Clinical Investigation
PublisherAmerican Society for Clinical Investigation
MetadataShow full item record
AbstractTherapies 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 itemhttp://hdl.handle.net/10713/16037
- Expression Pattern of HIF-1α and VEGF Supports Circumferential Application of Scatter Laser for Proliferative Sickle Retinopathy.
- Authors: Rodrigues M, Kashiwabuchi F, Deshpande M, Jee K, Goldberg MF, Lutty G, Semenza GL, Montaner S, Sodhi A
- Issue date: 2016 Dec 1
- An allosteric peptide inhibitor of HIF-1α regulates hypoxia-induced retinal neovascularization.
- Authors: Usui-Ouchi A, Aguilar E, Murinello S, Prins M, Gantner ML, Wright PE, Berlow RB, Friedlander M
- Issue date: 2020 Nov 10
- HIF-1alpha and HIF-2alpha are differentially activated in distinct cell populations in retinal ischaemia.
- Authors: Mowat FM, Luhmann UF, Smith AJ, Lange C, Duran Y, Harten S, Shukla D, Maxwell PH, Ali RR, Bainbridge JW
- Issue date: 2010 Jun 14
- HIF-2alpha-haploinsufficient mice have blunted retinal neovascularization due to impaired expression of a proangiogenic gene battery.
- Authors: Dioum EM, Clarke SL, Ding K, Repa JJ, Garcia JA
- Issue date: 2008 Jun
- Inhibition of retinal neovascularization by gene transfer of small interfering RNA targeting HIF-1alpha and VEGF.
- Authors: Jiang J, Xia XB, Xu HZ, Xiong Y, Song WT, Xiong SQ, Li Y
- Issue date: 2009 Jan