What is Vascular Endothelial Growth Factor (VEGF)?

Instructor: Shannon Compton

Shannon teaches Microbiology and has a Master's and a PhD in Biomedical Science. She also researches cancer and neurodegenerative diseases.

Vascular Endothelial Growth Factor (VEGF) is an important protein that helps to create blood and lymph vessels. This unique protein can also help tumors thrive, and when used correctly, may also work in cancer treatments.

VEGF Mechanism in Growth and Development

Multicellular organisms, like humans, have many complex systems that need attention. For example, we have to supply our tissues with oxygen and nutrients so that they can grow and develop properly. Our network of blood and lymph vessels helps with that. However, something needs to create or trigger this network when our tissues need oxygen supply. That's where vascular endothelial growth factor (VEGF) comes into play.

VEGF is a cell-produced protein that can create new blood vessels where none existed. This process is known as vasculogenesis. VEGF contributes to angiogenesis as well, which occurs when new blood vessels are created from pre-existing vessels. Some forms of VEGF can also stimulate lymphangiogenesis, the creation of new lymph vessels. The difference between vasculogenesis and angiogenesis is that vasculogenesis starts with individual cells, which become blood vessels in response to VEGF. In angiogenesis, the cells are already part of a blood vessel and VEGF simply causes a new blood vessel to grow from the old one.

Forms of VEGF

VEGF in its various forms is one of the signaling molecules that trigger a vasculogenic, angiogenic, or lymphangiogenic pathway. There are seven members in the VEGF family, each with different functions. VEGF-A was discovered first. The other forms are more recent discoveries.

  • VEGF-A: Creates new blood vessels during embryotic development, to repair injury, and after exercise (angiogenesis); widens blood vessels (vasodilation); and helps to mobilize various cells, such as macrophages and granulocytes (a category of white blood cells).
  • VEGF-B: Creates new blood vessels during embryotic development, contributing to formation of the muscular tissue in the heart; plays a role in the survival of new blood vessels; protects neurons in the cerebral cortex and retina during a stroke.
  • VEGF-C: Creates new lymph vessels (lymphangiogenesis); plays a role in vascular endothelial cell growth, production, and transition.
  • VEGF-D: Creates new lymph vessels, especially in developing lungs; mediates downstream VEGF angiogenic effects.
  • VEGF-E: Promotes epidermal (skin) regeneration by regulating keratinocyte function; mediates downstream VEGF angiogenic effects.
  • VEGF-F: Can be found in the venom of some snakes.
  • PlGF or PGF (placental growth factor): Participates in inflammatory processes; promotes adult pathological angiogenesis; provides therapeutic relief of coronary heart disease.

Figure 1. VEGF protein and receptors.
VEGF proteins and their target receptors.

VEGF Secretion

VEGF is secreted by tissues in response to certain conditions like hypoxia, which is a lack of oxygen. VEGF acts as a ligand. A ligand is a protein that will bind its target receptors on endothelial cells (the inside cellular lining of a tissue). Binding activates a series of molecules in the VEGF signaling pathway resulting in multiple changes within the endothelial cell. These changes will alter protein expression of the target cell.

One change is to initiate transcription of cell division signals (proliferation), while another is to initiate production of matrix metalloproteinases (MMPs). MMPs are a group of proteins that degrade the extracellular matrix (ECM) that surrounds all cells. The ECM gives cells a base on which to grow and also serves as a network to hold cells together in a tissue.

The endothelial cells can then migrate through the ECM toward the area of highest VEGF concentration. As the endothelial cells grow toward the tissue responsible for secreting VEGF, they mature (differentiate) into blood vessels. Once the oxygen supply is adequate, VEGF secretion stops. This makes endothelial cell proliferation and blood vessel growth stop as well.

What Triggers VEGF Secretion?

Oxygen deficiency is the main activator (trigger) of VEGF synthesis and secretion. When cells are deprived of oxygen, a signaling cascade is initiated which results in upregulation of VEGF. Growth-associated cytokines (chemical messengers) and proteins are also important for triggering VEGF synthesis and secretion. Another trigger occurs when cell receptors are stimulated. Two examples of stimulants include proteins from cancer-causing genes and tumor-suppressing genes. Both stimulants are important players in cancer initiation and inhibition.

What Inhibits VEGF Secretion?

Creating new blood vessels is costly for the organism. It takes energy and resources to replicate cells, create and secrete proteins, and build new blood vessels. Therefore, angiogenesis is tightly regulated through the interactions of pro-vascularization and anti-vascularization factors. Under steady-state conditions, the balance tips towards inhibiting neovascularization (growth of new blood vessels). However, during growth phases or when repair is needed, the balance is tipped in the direction of promoting neovascularization. These situations include revascularization following trauma, endometriosis, and tumor growth. Indeed, neovascularization is critical for cancer growth.

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