Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2024 May 9;13(10):2778.
doi: 10.3390/jcm13102778.

Beyond VEGF: Angiopoietin-Tie Signaling Pathway in Diabetic Retinopathy

Genesis Chen-Li  1 , Rebeca Martinez-Archer  1 , Andres Coghi  1 , José A Roca  2 , Francisco J Rodriguez  3 , Luis Acaba-Berrocal  4 , María H Berrocal  5 , Lihteh Wu  1   4
Affiliations
Review

Beyond VEGF: Angiopoietin-Tie Signaling Pathway in Diabetic Retinopathy

Genesis Chen-Li et al. J Clin Med. .

Abstract

Complications from diabetic retinopathy such as diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) constitute leading causes of preventable vision loss in working-age patients. Since vascular endothelial growth factor (VEGF) plays a major role in the pathogenesis of these complications, VEGF inhibitors have been the cornerstone of their treatment. Anti-VEGF monotherapy is an effective but burdensome treatment for DME. However, due to the intensive and burdensome treatment, most patients in routine clinical practice are undertreated, and therefore, their outcomes are compromised. Even in adequately treated patients, persistent DME is reported anywhere from 30% to 60% depending on the drug used. PDR is currently treated by anti-VEGF, panretinal photocoagulation (PRP) or a combination of both. Similarly, a number of eyes, despite these treatments, continue to progress to tractional retinal detachment and vitreous hemorrhage. Clearly there are other molecular pathways other than VEGF involved in the pathogenesis of DME and PDR. One of these pathways is the angiopoietin-Tie signaling pathway. Angiopoietin 1 (Ang1) plays a major role in maintaining vascular quiescence and stability. It acts as a molecular brake against vascular destabilization and inflammation that is usually promoted by angiopoietin 2 (Ang2). Several pathological conditions including chronic hyperglycemia lead to Ang2 upregulation. Recent regulatory approval of the bi-specific antibody, faricimab, may improve long term outcomes in DME. It targets both the Ang/Tie and VEGF pathways. The YOSEMITE and RHINE were multicenter, double-masked, randomized non-inferiority phase 3 clinical trials that compared faricimab to aflibercept in eyes with center-involved DME. At 12 months of follow-up, faricimab demonstrated non-inferior vision gains, improved anatomic outcomes and a potential for extended dosing when compared to aflibercept. The 2-year results of the YOSEMITE and RHINE trials demonstrated that the anatomic and functional results obtained at the 1 year follow-up were maintained. Short term outcomes of previously treated and treatment-naive eyes with DME that were treated with faricimab during routine clinical practice suggest a beneficial effect of faricimab over other agents. Targeting of Ang2 has been reported by several other means including VE-PTP inhibitors, integrin binding peptide and surrobodies.

Keywords: Tie2; angiopoietins; angiopoietin–tie pathway; diabetic macular edema; diabetic retinopathy; faricimab; retinal angiogenesis; retinal neovascularization.

PubMed Disclaimer

Conflict of interest statement

G.C.-L., R.M.-A., A.C. and L.A.-B. declare no conflicts of interest. M.H.B. has received lecture fees from Roche, Genentech and Iveric Bio. J.A.R. has received lecture fees from ROCHE. F.J.R. has received lecture fees from Bayer, Roche and Iveric Bio. L.W. has received lecture fees from Iveric Bio, Roche, Bayer and Lumibird Medical.

Figures

Figure 1
Figure 1
Summary of the relationship between hyperglycemia and Ang2.
Figure 2
Figure 2
Summary of the effects of Ang1 and Ang2 on the blood–retinal barrier.
See this image and copyright information in PMC

References

    1. Ogurtsova K., da Rocha Fernandes J.D., Huang Y., Linnenkamp U., Guariguata L., Cho N.H., Cavan D., Shaw J.E., Makaroff L.E. IDF Diabetes Atlas: Global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res. Clin. Pract. 2017;128:40–50. doi: 10.1016/j.diabres.2017.03.024. - DOI - PubMed
    1. Klein R., Klein B.E., Moss S.E. Visual impairment in diabetes. Ophthalmology. 1984;91:1–9. doi: 10.1016/S0161-6420(84)34337-8. - DOI - PubMed
    1. Williams R., Airey M., Baxter H., Forrester J., Kennedy-Martin T., Girach A. Epidemiology of diabetic retinopathy and macular oedema: A systematic review. Eye. 2004;18:963–983. doi: 10.1038/sj.eye.6701476. - DOI - PubMed
    1. Brown M.M., Brown G.C., Sharma S., Shah G. Utility values and diabetic retinopathy. Am. J. Ophthalmol. 1999;128:324–330. doi: 10.1016/S0002-9394(99)00146-4. - DOI - PubMed
    1. Javitt J.C., Aiello L.P., Chiang Y., Ferris F.L., 3rd, Canner J.K., Greenfield S. Preventive eye care in people with diabetes is cost-saving to the federal government. Implications for health-care reform. Diabetes Care. 1994;17:909–917. doi: 10.2337/diacare.17.8.909. - DOI - PubMed