Vascular Endothelial Growth Factor, or VEGF, is a signal protein that orchestrates the formation of blood vessels. In biology, a “pathway” describes a series of molecular events where a signal, like VEGF, interacts with various components within and between cells. This interaction ultimately leads to a specific cellular response, such as the growth of new blood vessels.
The Role of VEGF in the Body
Vascular Endothelial Growth Factor performs beneficial functions within the body, particularly in angiogenesis. Angiogenesis is the formation of new blood vessels from pre-existing ones, a process VEGF regulates. This process is essential during embryonic development for the formation of the circulatory system, known as vasculogenesis, and continues into adulthood for various restorative functions.
VEGF plays a role in repairing tissues after injury, such as a cut on the skin. It helps restore oxygen supply to tissues when blood circulation is inadequate, for example, after exercise in muscles. VEGF influences multiple aspects of wound repair, including promoting wound closure, aiding epidermal repair, and facilitating granulation tissue formation. It also contributes to the quality of repair, impacting the strength of the healed wound and the amount of scar tissue formed.
Mechanism of the VEGF Signal
The VEGF pathway operates through a sequence of interactions. Vascular Endothelial Growth Factor proteins bind to specialized protein receptors called VEGF receptors (VEGFRs) located on the outer membrane of cells, especially endothelial cells that line blood vessels. When a VEGF protein binds to its receptor, it causes two receptor molecules to come together, a process known as dimerization.
This dimerization activates an internal part of the receptor, specifically its tyrosine kinase domain, initiating a cascade of signals inside the cell. These signals are transmitted through various intracellular pathways, such as the Ras/MAPK pathway, which ultimately instruct the cell to perform actions like growing, dividing, migrating, or increasing the permeability of existing blood vessels. VEGFR-2 is the main receptor mediating many of these responses.
Connection to Disease Progression
While VEGF is essential for normal bodily functions, its pathway can become overactive or dysregulated, leading to several diseases. In cancer, tumors exploit the VEGF pathway to support their uncontrolled growth. They induce the formation of their own new blood vessels, a phenomenon called tumor angiogenesis. This new blood supply provides tumors with the oxygen and nutrients needed to grow larger and allows cancer cells to spread to other parts of the body, a process known as metastasis.
The VEGF pathway’s overactivity also contributes to specific eye diseases that impair vision. In “wet” age-related macular degeneration (AMD), abnormal and fragile new blood vessels grow beneath the retina in the macula, the part of the eye responsible for sharp, central vision. These vessels often leak fluid and blood, damaging light-sensing cells and leading to distorted or lost central vision. Similarly, in diabetic retinopathy, a complication of diabetes, high VEGF levels promote the growth of leaky, abnormal blood vessels in the retina and cause fluid accumulation, leading to conditions like diabetic macular edema and proliferative diabetic retinopathy.
Therapeutic Targeting of the VEGF Pathway
Understanding the role of the VEGF pathway in disease has led to the development of therapies designed to interrupt or block its activity. These treatments, known as anti-VEGF therapies, aim to halt the abnormal growth and leakage of blood vessels that contribute to various conditions. One strategy involves using monoclonal antibodies, engineered proteins that specifically bind to the VEGF protein itself. By “trapping” the VEGF protein, these antibodies prevent it from reaching and activating its receptors on cell surfaces, stopping the signaling cascade.
Examples include bevacizumab (Avastin) and ranibizumab (Lucentis). Bevacizumab is a full-length monoclonal antibody that binds to VEGF-A and is approved for intravenous use in certain cancers, though it is often used off-label for ocular conditions. Ranibizumab, a smaller antibody fragment, is approved for intravitreal injection in eye diseases like wet AMD and diabetic retinopathy.
Another approach uses recombinant fusion proteins that act as “decoy receptors.” Aflibercept (Eylea) is an example; it mimics natural VEGF receptors and binds to VEGF (and Placenta Growth Factor, PlGF) in the bloodstream. This binding sequesters VEGF proteins, preventing them from interacting with their actual receptors on endothelial cells. These anti-VEGF agents have improved outcomes for patients with wet AMD and diabetic retinopathy, helping preserve vision by reducing abnormal vessel growth and leakage in the eye.