HIF-1α and HIF-2α redundantly promote retinal neovascularization in patients with ischemic retinal disease
Jing Zhang, … , Silvia Montaner, Akrit Sodhi
Jing Zhang, … , Silvia Montaner, Akrit Sodhi
Published June 15, 2021
Citation Information: J Clin Invest. 2021;131(12):e139202. https://doi.org/10.1172/JCI139202.
View: Text | PDF
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

×

Figure 2

Expression of HIF-1α and HIF-2α and HIF-regulated angiogenic mediators in the ischemic retina of patients with sickle cell disease.

Options: View larger image (or click on image) Download as PowerPoint
Expression of HIF-1α and HIF-2α and HIF-regulated angiogenic mediators i...
(A) Fluorescein angiogram from a patient with PSR demonstrating areas of normal perfusion (pink arrow) posteriorly (i) and nonperfusion (blue arrow) peripherally (ii and iii); the margin between perfused and nonperfused retina demarcated in red. Areas without (ii) and with (iii) retinal NV (red arrows) are seen adjacent to one another. (B) Representative images from immunohistochemical analysis for the endothelial cell marker CD34 in posterior perfused and peripheral ischemic retina, the latter without and with NV (red arrows). In the posterior retina, vessels are noted in the superficial, intermediate, and deep vascular plexuses (pink arrows). In the ischemic retina (without NV), rare vessels are noted in the superficial and intermediate vascular plexuses (pink arrows), but vessels are absent in the deep vascular plexus (blue arrows). In ischemic retina with overlying retinal NV (red arrows), there was a complete absence of retinal vessels in all vascular plexuses (blue arrows). (C) IgG was used as a negative control. (D–G) Expression of the HIF-regulated angiogenic mediators VEGF (D) and ANGPTL4 (E), HIF-1 (F), and HIF-2α (G) in these same regions of sickle cell eyes. n = 5 eyes. GCL, ganglion cell layer; IPL, inner plexiform layer; INL, inner nuclear layer; OPL, outer plexiform layer; ONL, outer nuclear layer; RPE, retinal pigment epithelium. Scale bar: 100 μm.