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Year : 2019  |  Volume : 9  |  Issue : 4  |  Page : 213-215

The omnipresence of vascular endothelial growth factor in retinal diseases

Macula, Vitreous and Retina Associates of Costa Rica, San José, Costa Rica; Illinois Eye and Ear infirmary, University of Illinois, Chicago, IL, USA

Date of Web Publication13-Dec-2019

Correspondence Address:
Dr. Lihteh Wu
Macula, Vitreous and Retina Associates of Costa Rica, Primer Piso, Torre Mercedes, Paseo Colón, San José

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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/tjo.tjo_73_19

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How to cite this article:
Wu L. The omnipresence of vascular endothelial growth factor in retinal diseases. Taiwan J Ophthalmol 2019;9:213-5

How to cite this URL:
Wu L. The omnipresence of vascular endothelial growth factor in retinal diseases. Taiwan J Ophthalmol [serial online] 2019 [cited 2020 Jul 16];9:213-5. Available from: http://www.e-tjo.org/text.asp?2019/9/4/213/271489

More than seven decades ago, Michaelson [1] proposed that a diffusible and soluble factor X was responsible for retinal vascular growth during development and pathological states such as ischemic retinopathies. Many decades later, vascular endothelial growth factor (VEGF) was found to be Michaelson's elusive factor X. VEGF has multiple biologic properties including angiogenesis, increasing vascular permeability, neuroprotection, and inflammation.[2] Pharmacological inhibition of VEGF has revolutionized the treatment of blinding diseases such as diabetic macular edema (DME), proliferative diabetic retinopathy (PDR), retinopathy of prematurity (ROP), and exudative age-related macular degeneration (AMD).

ROP is one of the leading causes of childhood blindness. Taiwanese researchers have been at the forefront of research on ROP and VEGF inhibition.[3],[4],[5],[6] In this issue of the Journal, Sen et al. reported their results of 60 eyes with Zone 1 ROP that underwent treatment. Of these 60 eyes, 40 achieved a favorable anatomic outcome. Almost half of these 40 eyes received VEGF inhibitors as adjuncts to vitrectomy or laser photocoagulation, underscoring the important role that VEGF plays in ROP. These results are in line with the Taiwanese experience.[3],[5] Since intravitreal VEGF inhibitors lead to the suppression of serum VEGF levels, it is important to know the systemic implications of this finding.[6] It is reassuring that Fan et al.[4] showed that the neurodevelopmental outcomes of bevacizumab-treated children did not differ from those who did not receive bevacizumab.

Neovascular AMD is one of the main causes of visual loss in the elderly. Anti-VEGF drugs have revolutionized the management of this condition. In this issue of the Journal, Yang et al. report on 73 eyes with exudative AMD that had a follow-up of at least 4 years. Following a loading dose of three consecutive monthly injections of ranibizumab, the patients were followed on a modified treat and extend protocol. The injection interval was extended or shortened by 1-month interval. Eyes with persistent neovascular activity were eligible for rescue treatment with aflibercept. In this group of patients, the visual gains were maintained at 4 years, particularly those patients with a worse baseline visual acuity and older age. Yet not all patients with neovascular AMD respond equally to anti-VEGF drugs. In this issue of the Journal, Rodriguez et al. analyzed the response to ranibizumab according to polymorphisms in the CFH, HTRA1, and ARMS2 genes. They found that in their Colombian population, the response to treatment with ranibizumab differed according to the CFH genotype but not to ARMS2 and HTRA1 polymorphisms. Several polymorphisms in different genes, including the CFH, ARMS2, HTRA1, PEDF, VEGF, tumor necrosis factor-alpha, and interleukin-8 genes, have been associated with AMD in the Taiwanese population.[7],[8],[9],[10],[11],[12] To the best of my knowledge, there is currently no information on how genetics affects the response to anti-VEGF therapy in neovascular AMD in the Taiwanese population. This may represent an interesting avenue of research for Taiwanese researchers.

Over 150 years ago, Noyes [13] published his clinical observations of “retinitis by glycosuria”. It is noteworthy that Noyes stated that, “I am aware that disease of the retina has been found complicating diabetes mellitus, but cases of this kind are by no means common.” Unfortunately, the global incidence and prevalence of diabetes mellitus (DM) have reached epidemic proportions.[14] Taiwan is not an exception. According to the International Diabetes Federation, there were almost 2 million Taiwanese diabetic patients in 2017. There may be some light at the end of the tunnel as the incidence of DM peaked in 2012 at a rate of 9.04/1000 persons. By 2014, the incidence rate had dropped to 8.82/1000 persons.[15] All of these individuals will be at risk of developing diabetic retinopathy (DR) and DME.

The revolution in molecular biology has elucidated some of the underlying pathologic mechanisms in both DR and DME. VEGF plays an important role in the pathogenesis of both DR and DME.[16],[17] Nevertheless despite an intensive anti-VEGF treatment, approximately a third to two-thirds of patients with DME exhibit persistent DME at 6 months.[18],[19] Current alternatives for eyes that have a suboptimal response to anti-VEGF agents include intravitreal corticosteroids and pars plana vitrectomy (PPV). In this issue of the Journal, Chawan-Saad et al. and Flikier et al. thoroughly review these topics.

Chawan-Saad et al. analyzed the advantages and disadvantages of intravitreal corticosteroids when compared to intravitreal anti-VEGF drugs. Intravitreal corticosteroids are generally used as a second-line treatment for DME because of their less favorable safety profile. Nevertheless, certain patients may benefit from primary treatment with a corticosteroid intravitreal implant. These patients include those who have difficulty in maintaining a monthly appointment, particularly those with pseudophakic eyes, previously vitrectomized eyes, and eyes with long-standing DME.

Flikier et al. remind us that eyes with DME and vitreomacular traction clearly benefit from PPV as the primary treatment. In contrast, eyes with DME without tractional elements probably do not benefit from PPV. However, these views were based on eyes that had previously failed macular laser photocoagulation and had had persistent DME for a long time before being considered for PPV. Eyes with a shorter disease course may have better outcomes with PPV as the primary treatment and not as the salvage treatment.[20]

In this issue of the Journal, Wu et al. remind us that prior to the invention of the laser, most diabetic patients would become blind from PDR if they lived long enough. The introduction of panretinal photocoagulation (PRP) in routine clinical practice was a huge breakthrough that significantly decreased the rates of blindness in diabetic patients. However, PRP is not without adverse events. These include loss of peripheral visual fields, loss of color vision, loss of night vision, loss of contrast sensitivity, and exacerbation of DME. It is not surprising that interest in less destructive alternative treatments has been explored. Randomized clinical trials have shown the effectiveness of VEGF inhibitors in the treatment of PDR. The main drawback of anti-VEGF monotherapy for PDR is that these drugs need to be administered periodically for some time because of the chronic nature of the disease and the relatively short half-life of the VEGF inhibitors. Patients with PDR notoriously miss appointments and become hospitalized. Interruption of treatment can be catastrophic and lead to irreversible blindness. Combination treatment of PRP plus an anti-VEGF drug may be the treatment of choice for PDR.

In summary, the discovery of VEGF and the introduction of anti-VEGF agents in routine clinical practice have greatly improved the treatment outcomes of several blinding retinal disorders. The future looks bright, but several hurdles need to be overcome before we can truly once again exclaim “I am aware that disease of the retina has been found complicating diabetes mellitus, but cases of this kind are by no means common.”[13]

Financial support and sponsorship

Dr Lihteh Wu has received lecture and consultancy fees from Quantel Medical and Bayer. Quantel is a manufacturer of laser devices and Bayer commercializes aflibercept, an anti-VEGF drug used in the treatment of several retinal diseases.

Conflicts of interest

The author declares that there are no conflicts of interests of this paper.

  References Top

Michaelson IC. The mode of development of the vascular system of the retina, with some observations on its significance for certain retinal diseases. Trans Ophthalmol Soc U K 1948;68:137-80.  Back to cited text no. 1
Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev 1997;18:4-25.  Back to cited text no. 2
Cheng HC, Lee SM, Hsieh YT, Lin PK. Efficacy of intravitreal injection of anti-vascular endothelial growth factor agents for stage 4 retinopathy of prematurity. Retina 2015;35:660-6.  Back to cited text no. 3
Fan YY, Huang YS, Huang CY, Hsu JF, Shih CP, Hwang YS, et al. Neurodevelopmental outcomes after intravitreal bevacizumab therapy for retinopathy of prematurity: A prospective case-control study. Ophthalmology 2019;126:1567-77.  Back to cited text no. 4
Wu WC, Kuo HK, Yeh PT, Yang CM, Lai CC, Chen SN, et al. An updated study of the use of bevacizumab in the treatment of patients with prethreshold retinopathy of prematurity in taiwan. Am J Ophthalmol 2013;155:150-80.  Back to cited text no. 5
Wu WC, Shih CP, Lien R, Wang NK, Chen YP, Chao AN, et al. Serum vascular endothelial growth factor after bevacizumab or ranibizumab treatment for retinopathy of prematurity. Retina 2017;37:694-701.  Back to cited text no. 6
Lau LI, Chen SJ, Cheng CY, Yen MY, Lee FL, Lin MW, et al. Association of the Y402H polymorphism in complement factor H gene and neovascular age-related macular degeneration in Chinese patients. Invest Ophthalmol Vis Sci 2006;47:3242-6.  Back to cited text no. 7
Lin JM, Wan L, Tsai YY, Lin HJ, Tsai Y, Lee CC, et al. HTRA1 polymorphism in dry and wet age-related macular degeneration. Retina 2008;28:309-13.  Back to cited text no. 8
Lin JM, Wan L, Tsai YY, Lin HJ, Tsai Y, Lee CC, et al. Vascular endothelial growth factor gene polymorphisms in age-related macular degeneration. Am J Ophthalmol 2008;145:1045-51.  Back to cited text no. 9
Lin JM, Wan L, Tsai YY, Lin HJ, Tsai Y, Lee CC, et al. Pigment epithelium-derived factor gene Met72Thr polymorphism is associated with increased risk of wet age-related macular degeneration. Am J Ophthalmol 2008;145:716-21.  Back to cited text no. 10
Tsai YY, Lin JM, Wan L, Lin HJ, Tsai Y, Lee CC, et al. Interleukin gene polymorphisms in age-related macular degeneration. Invest Ophthalmol Vis Sci 2008;49:693-8.  Back to cited text no. 11
Wan L, Lin HJ, Tsai Y, Lee CC, Tsai CH, Tsai FJ, et al. Tumor necrosis factor-α gene polymorphisms in age-related macular degeneration. Retina 2010;30:1595-600.  Back to cited text no. 12
Noyes HD. Retinitis in glycosuria. Trans Am Ophthalmol Soc 1868;1:71-5.  Back to cited text no. 13
Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: Estimates for the year 2000 and projections for 2030. Diabetes Care 2004;27:1047-53.  Back to cited text no. 14
Hsu CC, Tu ST, Sheu WH. 2019 diabetes atlas: Achievements and challenges in diabetes care in Taiwan. J Formos Med Assoc 2019. pii: S0929-6646 (19) 30441-3.  Back to cited text no. 15
Funatsu H, Yamashita H, Ikeda T, Nakanishi Y, Kitano S, Hori S, et al. Angiotensin II and vascular endothelial growth factor in the vitreous fluid of patients with diabetic macular edema and other retinal disorders. Am J Ophthalmol 2002;133:537-43.  Back to cited text no. 16
Funatsu H, Yamashita H, Ikeda T, Mimura T, Eguchi S, Hori S, et al. Vitreous levels of interleukin-6 and vascular endothelial growth factor are related to diabetic macular edema. Ophthalmology 2003;110:1690-6.  Back to cited text no. 17
Bressler SB, Ayala AR, Bressler NM, Melia M, Qin H, Ferris FL 3rd, et al. Persistent macular thickening after ranibizumab treatment for diabetic macular edema with vision impairment. JAMA Ophthalmol 2016;134:278-85.  Back to cited text no. 18
Bressler NM, Beaulieu WT, Glassman AR, Blinder KJ, Bressler SB, Jampol LM, et al. Persistent macular thickening following intravitreous aflibercept, bevacizumab, or ranibizumab for central-involved diabetic macular edema with vision impairment: A secondary analysis of a randomized clinical trial. JAMA Ophthalmol 2018;136:257-69.  Back to cited text no. 19
Michalewska Z, Stewart MW, Landers MB 3rd, Bednarski M, Adelman RA, Nawrocki J, et al. Vitrectomy in the management of diabetic macular edema in treatment-naïve patients. Can J Ophthalmol 2018;53:402-7.  Back to cited text no. 20


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