Angiogenesis and the eye: A Journey to unlock the secrets of blood vessel growth

(Image Credit: AdobeStock/Design Cells)

Angiogenesis is the growth of blood vessels from the existing vasculature. The process occurs throughout life in both health and disease, beginning in utero and continuing on through old age. It is essential for normal growth and wound healing. No metabolically active tissue in the body is more than a few hundred micrometers from a blood capillary, which is formed by the process of angiogenesis.¹

It is a necessary process. It is also one that was found to work well in medicine when the understanding of its functionality in the body began to be understood. This is important because when angiogenesis becomes pathologic, it can impact sight among other bodily functions.

Angiogenesis is all encompassing in the body. Controlling angiogenesis was found during the past half century to have therapeutic value and this recognition generated a surge in research because it affects so many bodily processes. Stimulating angiogenesis can be therapeutic in ischemic heart disease, peripheral arterial disease, and wound healing. In contrast, decreasing or inhibiting angiogenesis can be therapeutic in cancer, ophthalmic conditions, rheumatoid arthritis, and other diseases. Capillaries grow and regress in healthy tissues according to functional demands. Exercise stimulates angiogenesis in skeletal muscle and heart. A lack of exercise leads to capillary regression. Capillaries grow in adipose tissue during weight gain and regress during weight loss.¹

The pioneers

Knowledge of the pathogenesis of tumors began to emerge around 1787, when John Hunter first described his observations of blood vessel growth.²

Published in 1794, his "A Treatise on the Blood, Inflammation, and Gun-Shot Wounds" described the correlation between vascularity and metabolic needs.²

Hunter commented, “In short, whenever Nature has considerable operations going on, and those are rapid, then we find the vascular system in a proportionable degree enlarged.”² Although he did not refer to this process as angiogenesis,^1,2 he was the first to recognize that overall regulation of angiogenesis follows a basic law of nature founded by Aristotle,³ which in essence is “form follows function.”

In the 1860s, investigators began to look at the morphology of the vascular network in human and animal tumors. It was not until 1907 that these vascular networks could be visualized with intraarterial injections of bismuth in oil allowed visualization of the vascular network in human and animal tumor specimens.⁴

This was followed by investigations to differentiate malignant and benign tumors based on their vascular patterns, an understanding of shedding of tumor emboli, and exploration of delivery of therapeutics into the tumors.⁴

It was during this period that the term angiogenesis was introduced to describe the process of blood vessel growth from pre-existing vasculature.

The pioneering work of Judah Folkman, MD, ushered angiogenesis into the modern era. He hypothesized that tumor growth is angiogenesis-dependent⁵ and that blocking angiogenesis could lead to tumor treatment and possible treatments for cancer. But this did not come without controversy.

His article published in 1971 in the New England Journal of Medicine⁵ caused such a negative uproar in the medical community that it quickly made him a pariah.⁶ Most top cancer researchers at the time thought tumor vasculature to be a mere response to inflammation rather than a necessary precondition for tumor growth. Even researchers who found Folkman’s angiogenesis hypothesis theoretically attacked it as irresponsibly speculative.⁶

In his article, Folkman also used the term anti-angiogenesis to mean “the prevention of new vessel sprouts from being recruited by a tumor.”⁵ The main take-aways were that⁶:

• Tumors cannot grow dangerously large unless they develop vascular networks.
• Tumors cannot build their own vascular networks, so they must trick their hosts into building such networks through angiogenesis.
• An angiogenesis inhibitor could therefore treat cancer effectively.

Folkman's hypothesis led to intensive research on angiogenesis and the development of angiogenesis inhibitors.The 1980s saw the discovery of key pro-angiogenic molecules like basic fibroblast growth factor and vascular endothelial growth factor (VEGF).⁶

Researchers began looking at angiogenesis inhibitors as therapeutic agents for cancer and other conditions. Investigations now are unraveling complex mechanisms of angiogenesis, developing novel therapies, and identifying new treatment targets.

Angiogenesis in the eye: how it works

Angiogenesis is essential for ocular development to ensure appropriate blood supply and function, wound healing, and a healthy vascular system.⁶

Conversely, pathological angiogenesis, involving endothelial cells and angiogenic factors, is a major contributor to vision loss in diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, and corneal neovascularization. Pathological angiogenesis involves the activation, proliferation, migration, and tube formation of vascular endothelial cells, leading to the formation of fragile and leaky blood vessels.¹

Key steps in Angiogenesis

The key steps involve the following activities:⁷

• Degradation of the extracellular matrix: Endothelial cells secrete enzymes that break down the surrounding matrix, allowing them to migrate.
• Endothelial cell proliferation and migration: Endothelial cells multiply and move towards the source of angiogenic stimuli.
• Formation of new blood vessels: Endothelial cells form new capillaries, which then mature into larger blood vessels.
• Vessel maturation and stabilization: The new blood vessels are stabilized by the recruitment of other cells, like pericytes, and the formation of a basement membrane.

Therapeutic Approaches

Current anti-angiogenic treatments for some of these conditions focus on blocking VEGF signaling or targeting other factors involved in angiogenesis. These include intraocular injections⁸ for wet age-related macular degeneration, diabetic retinopathy, retinal vein occlusion, diabetic macular edema, and retinopathy of prematurity.

Pegaptanib (Macugen, Eyetech), a pegylated RNA aptamer that inhibits VEGF-A165 was the first therapy introduced. This was followed by the current armamentarium that includes compounds that bind to VEGF: bevacizumab (Avastin, Genentech), a 149-kDa humanized monoclonal antibody that was first introduced to treated cancer; ranibizumab (Lucentis, Genentech), a recombinant humanized antibody fragment that binds to VEGF-A and prevents its interaction with VEGF receptors; aflibercept (Eylea, Regeneron), a recombinant fusion protein that binds to VEGF-A, VEGF-B, and placental growth factor (PIGF) and inhibits their signaling pathways; conbercept (Lumitin, Chengdu Kanghong Biotech Co.), a recombinant fusion protein that can trap all isoforms of VEGF-A, VEGF-B, PlGF, and VEGF-C; brolucizumab (Beovu, Novartis), a28-kDa single-chain antibody fragment targeting VEGF-A; and faricimab (Vabysmo, Genentech), a bispecific antibody targeting both VEGF-A and angiopoietin-2.⁸

Previously used therapies included laser photocoagulation performed to destroy abnormal blood vessels, particularly in diabetic retinopathy and photodynamic therapy involves injecting a photosensitizing drug, followed by laser treatment to selectively destroy choroidal neovascular tissue.⁸

Beyond the injectable treatments, the port delivery system (Susvimo, Roche) with ranibizumab, gene therapy, nanoparticles for drug delivery, and other targeted therapies are newest and future therapies.

The future

Angiogenesis is one of the key conditions for the proliferation, invasion, and metastasis of carcinomas, and anti-angiogenic treatment has gradually become a prevalent anti-tumor strategy with a criterion of vascular optimization. However, some common issues remain to be solved, such as insufficient therapeutic efficacy, reproducibility, and popularization of treatment modalities. These limitations encourage researchers to develop novel angiogenic inhibitor, explore the druggability of more targets, validate specific biomarkers, and optimize treatment administration, in order to break the “treatment deadlock” and strive more opportunities for cancer patients.⁹

With an in-depth understanding of tumor angiogenesis, tumor microenvironment, and drug resistance, these problems may be solved in the near future. As an emerging strategy, anti-angiogenic therapy will achieve more clinical benefits for cancer patients and anti-tumor therapy, and facilitate the clinical treatment of non-neoplastic angiogenesis-related diseases as well.⁹

References

1. Adair TH, Montani J-P. Angiogenesis. Chapter 1: Overview of angiogenesis. 2010; San Rafael, CA: Morgan & Claypool Life Sciences.

2. Hunter J. A treatise on the blood, inflammation and gunshot wounds. Palmer JF (Ed). 1794; Philadelphia: Raswell, Barrington, and Haswell, 1840; p. 195.

3. Aristotle on the parts of animals. W. Ogle (Trans.). London: Kegan Paul, Trench & Co., 1882.

4. Folkman, J. (2008). History of angiogenesis. In: Figg WD, Folkman J. (eds.) Angiogenesis. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-71518-6_1

5. Folkmann J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285:1182-1186.DOI: 10.1056/NEJM197111182852108

6. Folkman’s Legacy of Bold and Creative Thinking Endures. The Angiogenesis Foundation. 2014;Mar 19.

7. Dreyfuss JL, Giordano RJ, Regatieri CV. Ocular angiogenesis. J Ophthalmol. 2015;2015:892043. doi: 10.1155/2015/892043

8. Chen R, Zhu J, Hu J, Li X. Antiangiogenic therapy for ocular diseases: current status and challenges. Med Comm—Future Medicine. 2023; https://doi.org/10.1002/mef2.33

9. Liu ZL, Chen HH, Zheng LL,et al. Angiogenic signaling pathways and anti-angiogenic therapy for cancer. Sig Transduct Target Ther. 2023;8:198. https://doi.org/10.1038/s41392-023-01460-1