On the surface of our cells are specialized proteins called receptors, which act like docking stations for specific signals. These receptors receive messages from molecules known as growth factors. This lock-and-key system ensures only a specific growth factor can fit its matching receptor to transmit a signal into the cell. One such receptor is the Vascular Endothelial Growth Factor Receptor 1, or VEGFR-1.
The name provides clues to its location and purpose. “Vascular endothelial” refers to the thin layer of endothelial cells that line the interior surface of all blood vessels. As a growth factor receptor, VEGFR-1 is part of a communication network that tells these cells how to behave. It is one of several receptors that respond to signals from the Vascular Endothelial Growth Factor (VEGF) family of molecules.
The Function of VEGFR-1 in the Body
The primary process involving VEGFR-1 is angiogenesis, the formation of new blood vessels from pre-existing ones. This activity is required for many normal bodily functions, including embryonic development, tissue growth, and wound healing. When a tissue is injured, it needs a new supply of blood to deliver oxygen and nutrients for repair, and angiogenesis provides the pathway for this.
VEGFR-1 has a complex and dual role in controlling vessel formation. While it possesses a weak ability to transmit signals, its more prominent function is as a “decoy receptor.” This is because VEGFR-1 has a very high affinity for the growth factor VEGF-A, binding to it about ten times more tightly than its more powerful sibling receptor, VEGFR-2.
By binding so strongly to VEGF-A, VEGFR-1 sequesters the growth factor, preventing it from activating VEGFR-2, which is the primary driver of signals that lead to endothelial cell growth. This regulatory function helps to fine-tune the process, maintaining a balance between promoting and inhibiting blood vessel growth. This is evident during embryonic development, where the absence of VEGFR-1 leads to disorganized and excessive vessel growth.
Soluble forms of VEGFR-1, which are not attached to the cell surface and circulate freely, can also trap VEGF-A, contributing to this negative regulation. The receptor can also be activated by other growth factors, like Placental Growth Factor (PlGF), which adds another layer to its regulatory control in different biological contexts.
The Role in Disease Development
In various diseases, the regulated function of VEGFR-1 can be disrupted, turning its processes into drivers of pathology. Cancer is a primary example, as tumors require a dedicated blood supply to grow. To achieve this, tumors exploit the body’s natural angiogenesis mechanisms, and VEGFR-1 plays a part in this tumor-associated vessel growth.
In cancer, VEGFR-1 is not only found on the endothelial cells of the tumor’s blood vessels but can also be expressed directly on some cancer cells. When expressed on tumor cells, its activation can promote their survival and migration. VEGFR-1 activation also helps recruit other cell types, such as certain immune cells, into the tumor’s vicinity, which can create an environment that supports tumor progression.
Beyond cancer, VEGFR-1 is implicated in other conditions characterized by abnormal blood vessel growth, such as the wet form of age-related macular degeneration (AMD). In this leading cause of vision loss, abnormal and leaky blood vessels grow in the retina. VEGFR-1 is involved in this pathological process, contributing to the inflammation and fluid leakage that damage sight.
Another condition linked to VEGFR-1 is pre-eclampsia, a serious complication of pregnancy. In pre-eclampsia, the placenta produces high levels of soluble VEGFR-1 (sVEGFR-1). This excess sVEGFR-1 traps circulating VEGF-A in the mother’s bloodstream, which causes widespread endothelial dysfunction, leading to the hypertension and organ damage seen in the condition.
Medical Therapies Targeting VEGFR-1
The involvement of VEGFR-1 in various diseases has made it a target for medical intervention. Scientists have developed targeted therapies designed to interfere with the VEGFR-1 signaling pathway. These treatments are engineered to act on specific molecular targets involved in the growth of abnormal cells.
One strategy involves using drugs that physically block the receptor, such as monoclonal antibodies. By attaching to the receptor, the antibody acts as a shield, preventing a growth factor like VEGF-A from fitting into its lock. This blockade inhibits the signals that would otherwise promote angiogenesis or tumor cell survival.
A second approach uses a “ligand trap,” where therapeutic molecules circulate in the bloodstream and catch VEGF growth factors before they reach their receptors. These traps are often fusion proteins that mimic the binding portion of the VEGFR-1 receptor. Because of VEGFR-1’s high affinity for VEGF, these traps are very effective at sequestering the growth factors.
These therapeutic strategies are applied in the treatment of certain cancers and eye diseases like wet AMD. By disrupting the VEGFR-1 pathway, these drugs can help starve tumors of their blood supply or reduce the abnormal vessel growth that causes vision loss.
Differentiating from Other VEGF Receptors
VEGFR-1 is a member of a small family of related receptors, and understanding its role requires comparing it to its siblings, primarily VEGFR-2 and VEGFR-3. While they all respond to signals from the VEGF family, they have distinct functions and allow for precise control over the body’s vessel systems.
VEGFR-2 is the principal driver of angiogenesis. When VEGF-A binds to VEGFR-2, it initiates a strong cascade of signals inside the endothelial cell, powerfully promoting the steps in building new blood vessels. In contrast, VEGFR-1’s signaling is much weaker and, as a decoy, it functions to modulate the powerful effects of VEGFR-2.
VEGFR-3 has a different primary domain of operation. Its main role is in lymphangiogenesis, which is the formation of lymphatic vessels. The lymphatic system is a network separate from the blood circulatory system that helps rid the body of toxins and waste. VEGFR-3 responds to different growth factors (VEGF-C and VEGF-D) to control the development of these lymphatic channels.