For citation: Neziri B, Kutllovci N, Salihu A, Durmishi S, Shabani A. Angiogenesis Induced by HIF1α and VEGF as a Pathophysiological Cause of Glaucoma. International Journal of Biomedicine. 2025;15(2):247-252. doi:10.21103/Article15(2)_RA2
Originally published June 5, 2025
Glaucoma, a group of ocular disorders characterized by progressive optic nerve damage and vision loss, presents a significant global health challenge. It is closely associated with elevated intraocular pressure, retinal ganglion cell (RGC) degeneration, and hypoxia-induced damage. Hypoxia-inducible factor 1-alpha (HIF-1α) is a crucial regulator in cellular adaptation to reduced oxygen conditions (hypoxia). In glaucoma, HIF-1α demonstrates a complex influence, extending beyond its role in upregulating vascular endothelial growth factor (VEGF) expression. This transcription factor may also contribute to pathological processes, including aberrant blood vessel formation, inflammatory cascades, and oxidative stress mechanisms associated with the disease.
This deleterious cycle of hypoxia, angiogenesis, and oxidative stress contributes to RGC apoptosis and optic nerve deterioration. The similarities between glaucoma and other vascular-related ocular diseases, such as diabetic retinopathy, suggest that anti-VEGF therapies could be efficacious in managing glaucoma.
Recent research highlights the critical role of angiogenesis as a factor exacerbating glaucoma. HIF-1α, a key regulator of cellular responses to hypoxia, plays a pivotal role by promoting VEGF expression, which drives abnormal blood vessel growth, inflammation, and oxidative stress. This vicious cycle of hypoxia, angiogenesis, and oxidative stress contributes to RGC apoptosis and optic nerve deterioration. Thus, understanding the interplay between HIF-1α, VEGF, angiogenesis, and oxidative stress is crucial for developing targeted interventions to preserve vision, reduce inflammation, and mitigate neurodegeneration in glaucoma.
Key Messages
This research delineates the intricate relationships among HIF-1α, angiogenesis, and oxidative stress as causes of glaucoma, thereby advancing our comprehension of the fundamental mechanisms underlying glaucoma. Such insights are anticipated to be instrumental in the development of targeted therapeutic strategies aimed at preserving visual acuity, reducing inflammatory responses, and impeding neurodegenerative processes.
- Weinreb RN, Aung T, Medeiros FA. The pathophysiology and treatment of glaucoma: a review. JAMA. 2014 May 14;311(18):1901-11. doi: 10.1001/jama.2014.3192. PMID: 24825645; PMCID: PMC4523637.
- Bilous V. PRODUCTION AND APPLICATION OF ANGIOSTATINS FOR THE TREATMENT OF OCULAR NEOVASCULAR DESEASES. Biotechnologia Acta.2021;14(1):5-24.
- Sharif NA. Therapeutic Drugs and Devices for Tackling Ocular Hypertension and Glaucoma, and Need for Neuroprotection and Cytoprotective Therapies. Front Pharmacol. 2021 Sep 17;12:729249. doi: 10.3389/fphar.2021.729249. PMID: 34603044; PMCID: PMC8484316.
- Krock BL, Skuli N, Simon MC. Hypoxia-induced angiogenesis: good and evil. Genes Cancer. 2011 Dec;2(12):1117-33. doi: 10.1177/1947601911423654. PMID: 22866203; PMCID: PMC3411127.
- Lee D, Tomita Y, Miwa Y, Kunimi H, Nakai A, Shoda C, Negishi K, Kurihara T. Recent Insights into Roles of Hypoxia-Inducible Factors in Retinal Diseases. Int J Mol Sci. 2024 Sep 21;25(18):10140. doi: 10.3390/ijms251810140. PMID: 39337623; PMCID: PMC11432567.
- Subhani S, Vavilala DT, Mukherji M. HIF inhibitors for ischemic retinopathies and cancers: options beyond anti-VEGF therapies. Angiogenesis. 2016 Jul;19(3):257-73. doi: 10.1007/s10456-016-9510-0. Epub 2016 May 4. PMID: 27146677.
- Tham YC, Li X, Wong TY, Quigley HA, Aung T, Cheng CY. Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis. Ophthalmology. 2014 Nov;121(11):2081-90. doi: 10.1016/j.ophtha.2014.05.013. Epub 2014 Jun 26. PMID: 24974815.
- Morrison JC, Cepurna Ying Guo WO, Johnson EC. Pathophysiology of human glaucomatous optic nerve damage: insights from rodent models of glaucoma. Exp Eye Res. 2011 Aug;93(2):156-64. doi: 10.1016/j.exer.2010.08.005. Epub 2010 Aug 11. PMID: 20708000; PMCID: PMC3010442.
- Husain S, Leveckis R. Pharmacological regulation of HIF-1α, RGC death, and glaucoma. Curr Opin Pharmacol. 2024 Aug;77:102467. doi: 10.1016/j.coph.2024.102467. Epub 2024 Jun 18. PMID: 38896924.
- Coorey NJ, Shen W, Chung SH, Zhu L, Gillies MC. The role of glia in retinal vascular disease. Clin Exp Optom. 2012 May;95(3):266-81. doi: 10.1111/j.1444-0938.2012.00741.x. Epub 2012 Apr 22. PMID: 22519424.
- Nebbioso M, Franzone F, Lambiase A, Bonfiglio V, Limoli PG, Artico M, Taurone S, Vingolo EM, Greco A, Polimeni A. Oxidative Stress Implication in Retinal Diseases-A Review. Antioxidants (Basel). 2022 Sep 10;11(9):1790. doi: 10.3390/antiox11091790. PMID: 36139862; PMCID: PMC9495599.
- Cheng L, Yu H, Yan N, Lai K, Xiang M. Hypoxia-Inducible Factor-1α Target Genes Contribute to Retinal Neuroprotection. Front Cell Neurosci. 2017 Feb 27;11:20. doi: 10.3389/fncel.2017.00020. PMID: 28289375; PMCID: PMC5326762.
- Lucchesi M. Retinopathy of Prematurity and Glaucoma: possible strategies to prevent Neovascularization and Neurodegeneration. 2023. [10.25434/lucchesi-martina_phd2023].
- Urbonavičiūtė D, Buteikienė D, Janulevičienė I. A Review of Neovascular Glaucoma: Etiology, Pathogenesis, Diagnosis, and Treatment. Medicina (Kaunas). 2022 Dec 18;58(12):1870. doi: 10.3390/medicina58121870. PMID: 36557072; PMCID: PMC9787124.
- Rohowetz LJ, Kraus JG, Koulen P. Reactive Oxygen Species-Mediated Damage of Retinal Neurons: Drug Development Targets for Therapies of Chronic Neurodegeneration of the Retina. Int J Mol Sci. 2018 Oct 27;19(11):3362. doi: 10.3390/ijms19113362. PMID: 30373222; PMCID: PMC6274960.
- Ekici E, Moghimi S. Advances in understanding glaucoma pathogenesis: A multifaceted molecular approach for clinician scientists. Mol Aspects Med. 2023 Oct 27;94:101223. doi: 10.1016/j.mam.2023.101223. Epub ahead of print. PMID: 39492376.
- Mammadzada P, Corredoira PM, André H. The role of hypoxia-inducible factors in neovascular age-related macular degeneration: a gene therapy perspective. Cell Mol Life Sci. 2020 Mar;77(5):819-833. doi: 10.1007/s00018-019-03422-9. Epub 2019 Dec 31. PMID: 31893312; PMCID: PMC7058677.
- Potilinski MC, Lorenc V, Perisset S, Gallo JE. Mechanisms behind Retinal Ganglion Cell Loss in Diabetes and Therapeutic Approach. Int J Mol Sci. 2020 Mar 28;21(7):2351. doi: 10.3390/ijms21072351. PMID: 32231131; PMCID: PMC7177797.
- Münch TA, da Silveira RA, Siegert S, Viney TJ, Awatramani GB, Roska B. Approach sensitivity in the retina processed by a multifunctional neural circuit. Nat Neurosci. 2009 Oct;12(10):1308-16. doi: 10.1038/nn.2389. Epub 2009 Sep 6. PMID: 19734895.
- Pesce NA. MOLECULAR MECHANISMS OF ANGIOGENESIS-RELATED OCULAR DISEASES IN PRECLINICAL MODELS. 2021. [10.25434/pesce-noemi-anna_phd2021].
- Foxton RH, Finkelstein A, Vijay S, Dahlmann-Noor A, Khaw PT, Morgan JE, Shima DT, Ng YS. VEGF-A is necessary and sufficient for retinal neuroprotection in models of experimental glaucoma. Am J Pathol. 2013 Apr;182(4):1379-90. doi: 10.1016/j.ajpath.2012.12.032. Epub 2013 Feb 12. PMID: 23416159; PMCID: PMC3608027.
- Kuang G, Halimitabrizi M, Edziah AA, Salowe R, O'Brien JM. The potential for mitochondrial therapeutics in the treatment of primary open-angle glaucoma: a review. Front Physiol. 2023 Aug 2;14:1184060. doi: 10.3389/fphys.2023.1184060. PMID: 37601627; PMCID: PMC10433652.
- Gu C, Lhamo T, Zou C, Zhou C, Su T, Draga D, Luo D, Zheng Z, Yin L, Qiu Q. Comprehensive analysis of angiogenesis-related genes and pathways in early diabetic retinopathy. BMC Med Genomics. 2020 Sep 29;13(1):142. doi: 10.1186/s12920-020-00799-6. PMID: 32993645; PMCID: PMC7526206.
- Kong Y, Liu PK, Li Y, Nolan ND, Quinn PMJ, Hsu CW, Jenny LA, Zhao J, Cui X, Chang YJ, Wert KJ, Sparrow JR, Wang NK, Tsang SH. HIF2α activation and mitochondrial deficit due to iron chelation cause retinal atrophy. EMBO Mol Med. 2023 Feb 8;15(2):e16525. doi: 10.15252/emmm.202216525. Epub 2023 Jan 16. PMID: 36645044; PMCID: PMC9906391.
- Begines B, Ortiz T, Pérez-Aranda M, Martínez G, Merinero M, Argüelles-Arias F, Alcudia A. Polymeric Nanoparticles for Drug Delivery: Recent Developments and Future Prospects. Nanomaterials (Basel). 2020 Jul 19;10(7):1403. doi: 10.3390/nano10071403. PMID: 32707641; PMCID: PMC7408012.
- Tulsawani R, Kelly LS, Fatma N, Chhunchha B, Kubo E, Kumar A, Singh DP. Neuroprotective effect of peroxiredoxin 6 against hypoxia-induced retinal ganglion cell damage. BMC Neurosci. 2010 Oct 5;11:125. doi: 10.1186/1471-2202-11-125. PMID: 20923568; PMCID: PMC2964733.
- Buonfiglio F, Böhm EW, Pfeiffer N, Gericke A. Oxidative Stress: A Suitable Therapeutic Target for Optic Nerve Diseases? Antioxidants (Basel). 2023 Jul 20;12(7):1465. doi: 10.3390/antiox12071465. PMID: 37508003; PMCID: PMC10376185.
- Fong GH. Mechanisms of adaptive angiogenesis to tissue hypoxia. Angiogenesis. 2008;11(2):121-40. doi: 10.1007/s10456-008-9107-3. Epub 2008 Mar 10. PMID: 18327686.
- Kang EY, Liu PK, Wen YT, Quinn PMJ, Levi SR, Wang NK, Tsai RK. Role of Oxidative Stress in Ocular Diseases Associated with Retinal Ganglion Cells Degeneration. Antioxidants (Basel). 2021 Dec 5;10(12):1948. doi: 10.3390/antiox10121948. PMID: 34943051; PMCID: PMC8750806.
- Vernazza S, Oddone F, Tirendi S, Bassi AM. Risk Factors for Retinal Ganglion Cell Distress in Glaucoma and Neuroprotective Potential Intervention. Int J Mol Sci. 2021 Jul 27;22(15):7994. doi: 10.3390/ijms22157994. PMID: 34360760; PMCID: PMC8346985.
- Ju WK, Kim KY, Lindsey JD, Angert M, Patel A, Scott RT, Liu Q, Crowston JG, Ellisman MH, Perkins GA, Weinreb RN. Elevated hydrostatic pressure triggers release of OPA1 and cytochrome C, and induces apoptotic cell death in differentiated RGC-5 cells. Mol Vis. 2009;15:120-34. Epub 2009 Jan 19. PMID: 19169378; PMCID: PMC2629709.
- Izzotti A, Bagnis A, Saccà SC. The role of oxidative stress in glaucoma. Mutat Res. 2006 Mar;612(2):105-14. doi: 10.1016/j.mrrev.2005.11.001. Epub 2006 Jan 18. PMID: 16413223.
- Sim RH, Sirasanagandla SR, Das S, Teoh SL. Treatment of Glaucoma with Natural Products and Their Mechanism of Action: An Update. Nutrients. 2022 Jan 26;14(3):534. doi: 10.3390/nu14030534. PMID: 35276895; PMCID: PMC8840399.
- Kuiper E.J., Van Nieuwenhoven F.A., de Smet M.D., van Meurs J.C., Tanck M.W., Oliver N., Klaassen I., Van Noorden C.J., Goldschmeding R., Schlingemann R.O. The angio-fibrotic switch of VEGF and CTGF in proliferative diabetic retinopathy. PLoS ONE. 2008;3:e2675. doi: 10.1371/journal.pone.0002675
- Stevenson W., Cheng S.F., Dastjerdi M.H., Ferrari G., Dana R. Corneal neovascularization and the utility of topical VEGF inhibition: Ranibizumab (Lucentis) vs bevacizumab (Avastin) Ocul. Surf. 2012;10:67–83. doi: 10.1016/j.jtos.2012.01.005.
- Ruan Y, Jiang S, Musayeva A, Gericke A. Oxidative Stress and Vascular Dysfunction in the Retina: Therapeutic Strategies. Antioxidants (Basel). 2020 Aug 17;9(8):761. doi: 10.3390/antiox9080761. PMID: 32824523; PMCID: PMC7465265.
- Malek G, Busik J, Grant MB, Choudhary M. Models of retinal diseases and their applicability in drug discovery. Expert Opin Drug Discov. 2018 Apr;13(4):359-377. doi: 10.1080/17460441.2018.1430136. Epub 2018 Jan 30. PMID: 29382242; PMCID: PMC6192033.
- Li W, Zhang J. Therapeutic Targets for Diabetic Retinopathy: A Translational Approach. Elsevier Health Sciences, Jan 12, 2023 - Medical - 325 pages.
- Drzyzga Ł, Śpiewak D, Dorecka M, Wyględowska-Promieńska D. Available Therapeutic Options for Corneal Neovascularization: A Review. Int J Mol Sci. 2024 May 17;25(10):5479. doi: 10.3390/ijms25105479. PMID: 38791518; PMCID: PMC11121997.
- Solipuram V, Soltani R, Venkatesulu BP, Annam S, Alavian F, Ghasemi S. Efficacy of Anti-VEGF Drugs Based Combination Therapies in Recurrent Glioblastoma: Systematic Review and Meta-Analysis. Curr Rev Clin Exp Pharmacol. 2024;19(2):173-183. doi: 10.2174/2772432817666220517163609. PMID: 35585804.
Download Article
Received February 12, 2025.
Accepted March 23, 2025.
©2025 International Medical Research and Development Corporation.