Vascular Endothelial Growth Factor A, commonly known as VEGFA, is a protein produced by many cells throughout the body. It functions as a signaling molecule, instructing cells to form new blood vessels, a process known as angiogenesis. Its primary action involves binding to specific receptors on endothelial cells, which are the cells lining blood vessels, thereby triggering various cellular responses that lead to vessel formation.
VEGFA’s Normal Functions
VEGFA performs various beneficial roles within the body, contributing to healthy physiological processes. During embryonic development, VEGFA plays a significant role in vasculogenesis, the initial formation of the entire circulatory system. It guides the differentiation of endothelial cells and the creation of scaffolding structures that form the primary capillary plexus, from which the local vasculature develops. Without proper VEGFA expression, embryonic blood vessel formation can be abnormal, sometimes leading to embryonic death.
The protein also participates in wound healing, where it signals for new blood vessels to grow into damaged tissues. These newly formed vessels supply oxygen and nutrients, which are necessary for tissue repair and regeneration. Furthermore, VEGFA is involved in normal physiological processes such as the female reproductive cycle. It contributes to the growth of the uterine lining and supports processes like ovulation and placental development.
VEGFA’s Role in Disease
While VEGFA serves beneficial purposes, its dysregulation can contribute to several diseases, particularly those involving abnormal blood vessel growth. In the context of cancer, tumors often exploit the VEGFA pathway to promote their own growth and spread. Tumors produce high levels of VEGFA, which stimulates the formation of new blood vessels within and around the tumor, providing it with a blood supply to deliver oxygen and nutrients for rapid proliferation. This process, known as tumor angiogenesis, is a significant factor in tumor development, invasion, and metastasis, allowing cancer cells to spread to distant parts of the body.
Excessive VEGFA activity is also implicated in eye diseases that cause vision loss. In “wet” age-related macular degeneration (AMD), abnormal and leaky blood vessels grow beneath the retina. This choroidal neovascularization, driven by VEGFA, can lead to fluid leakage, hemorrhage, and scarring, resulting in distorted or lost central vision. Similarly, in diabetic retinopathy, high levels of VEGFA contribute to retinal neovascularization, where new blood vessels form on the surface of the retina. These vessels are prone to bleeding and can lead to vitreous hemorrhage and retinal detachment, ultimately impairing vision.
Therapeutic Inhibition of VEGFA
Given VEGFA’s involvement in various diseases, therapies have been developed to inhibit its activity. Anti-VEGF therapy involves drugs that block the function of VEGFA, thereby preventing or reducing abnormal blood vessel growth. These drugs act as inhibitors by binding to VEGFA itself or to its receptors, stopping the signaling cascade that promotes angiogenesis. The goal is to starve tumors of their blood supply or to prevent the formation of leaky vessels in the eye.
Specific anti-VEGF drugs are administered depending on the condition. For cancers, bevacizumab is a humanized monoclonal antibody that binds to and neutralizes all isoforms of VEGFA, preventing it from interacting with its receptors. This drug is given intravenously to patients with various solid tumors.
In eye conditions like wet AMD and diabetic retinopathy, drugs such as ranibizumab and aflibercept are used. Ranibizumab is an antibody fragment that binds to VEGFA, while aflibercept is a fusion protein that acts as a “decoy receptor,” binding to VEGFA, VEGF-B, and placental growth factor, effectively sequestering them. These ocular anti-VEGF medications are administered directly into the vitreous of the eye through intravitreal injections.