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What is Angiogenesis? - Definition, Factors & Quiz

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Shannon Compton

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

Angiogenesis is the process of creating new blood vessels from preexisting blood vessels. The process is vital for the growth and development of an organism, as well as in wound repair. In addition, angiogenesis is a therapeutic target in many diseases. This lesson will focus on each of these roles.

Angiogenesis: An Introduction

Angiogenesis is defined as the growth of new blood vessels. This process is essential for healing, growth, development, and maintenance. The body controls angiogenesis by balancing stimulatory and inhibitory factors. Disease occurs when this delicate balance is disturbed.

When this balance is disrupted, the result is either too much or too little angiogenesis. Many debilitating conditions are associated with abnormal blood vessel growth. Indeed, overgrowth or lack of growth may be the cause of many medical conditions, including cancer, skin diseases, age-related blindness, diabetic wounds that do not heal, heart disease, and strokes.

Historical Note

'In short, whenever Nature has considerable operations going on, and those are rapid, then we find the vascular system in a proportionable degree enlarged.' These words are attributed to John Hunter, a Scottish anatomist and surgeon. He is describing what would later be called angiogenesis. He suggested that areas of high metabolic requirement, i.e. those needing a good nutrient supply, also have a lot of blood vessels.

The first person to actually suggest that tissue growth depends on angiogenesis was Judah Folkman (Figure 1). In 1971, he published an article hypothesizing that tumor growth is angiogenesis-dependent. He also suggested that inhibiting angiogenesis could be a cure for cancer. Establishing a link between angiogenesis and cancer drove concentrated research in the field. As a result, we now have a fairly good grasp of how angiogenesis works normally and what goes wrong in disease processes.

Figure 1: Portrait of Judah Folkman
Image of Judah Folkman

Types of Angiogenesis

There are two types of angiogenesis, sprouting and intussusceptive. These both occur in an organism growing in the uterus (in utero), in a growing organism, and in adults. Sprouting angiogenesis was discovered over 200 years ago and is better understood. It has only been twenty years since intussusceptive angiogenesis was discovered.

Figure 2 shows a visual comparison of both types. In sprouting angiogenesis, the new blood vessels branch off of or sprout from the main blood vessel. This looks much like roots on a plant. In contrast, intussusceptive angiogenesis happens when a blood vessel splits and then new vessels grow into the center. Intussusceptive means 'to take within.' Both types of angiogenesis are thought to occur in virtually all tissues and organs.

Figure 2: Types of Angiogenesis
Types of angiogenesis

Angiogenesis Mechanism

Why does the body grow new blood vessels? The primary reason is to alleviate hypoxia, which is the condition when cells are starved of oxygen. This can happen for several reasons, including growth, injury, or blocked arteries. How does the body know hypoxia is happening and how does it make new blood vessels grow?

The body has mechanisms to sense when oxygen levels are low. These oxygen sensing mechanisms will sound the alarm by secreting a key pro-angiogenic growth factor called vascular endothelial growth factor (VEGF). VEGF secretion starts a signal cascade. The effects of this cascade include the growth of new blood vessels into areas where there were none. An important part of this process is to break down existing tissue so that the new blood vessel has a place in which to grow. This is not unlike clearing a piece of land in order to build a highway. However, instead of bulldozers, the body uses special proteins (proteolytic enzymes) to break down any tissues that are in the way of vessel growth.

How does the body know when it has grown enough blood vessels and how does it stop the growth? Special cells called endothelial tip cells guide the growing sprout through the body's tissues. These cells can detect the levels of VEGF and grow towards the highest concentration they can find. Behind these tip cells, the new blood vessel is widening and filling with oxygenated blood. This brings much needed oxygen to the hypoxic tissues. Once the local tissues are receiving enough oxygen, VEGF levels return to near normal. This stops the process of angiogenesis.

Angiogenesis Is Controlled by On/Off Switches

The previous section described the process of angiogenesis in a very basic way. In truth, angiogenesis is much more complicated. Not necessarily in what happens, but in how many players are involved. Angiogenesis is actually regulated by a vast number of on and off switches. These switches are delicately balanced.

Increasing the number of pro-angiogenic factors (on switches) can start or speed up angiogenesis, while decreasing the number of pro-angiogenic factors can slow it down or stop angiogenesis. In addition, there are also off switches (anti-angiogenic factors) that decrease or stop angiogenesis. Anti-angiogenic factors work in opposition to pro-angiogenic factors. Thus, whether or not angiogenesis is occurring depends on how many on switches and off switches are present. The amounts of these switches that are produced in a tissue are regulated by oxygen need. However, there are disease processes that occur, and these can be completely independent of oxygen levels. Figures 3 and 4 list on and off switches.

Figure 3: Pro-angiogenic Factors
Pro-angiogenic Factors

Figure 4: Anti-angiogenic Factors
Anti-angiogenic Factors

Angiogenesis in Disease

When the body loses control over angiogenesis, disease happens. We call these angiogenesis-dependent diseases. They can be a result of too much vessel growth or result from a lack of growth.

Over seventy diseases are associated with excessive angiogenesis (too much growth). These include cancer, diabetic blindness, age-related macular degeneration, rheumatoid arthritis, psoriasis, and others. These diseases are able to produce massive amounts of pro-angiogenic factors. Because of this, they are able to overwhelm the effects of anti-angiogenic factors. Medications designed to treat the vascular overgrowth that occurs in these conditions are called antiangiogenic therapies.

Insufficient angiogenesis (too little growth) occurs less often and is associated with heart disease, stroke, and chronic wounds, such as those that affect diabetics. In affected tissues, the body cannot produce enough pro-angiogenic factors. This leads to poor circulation and oxygen starvation on affected tissues. Tissue death can result.

Therapeutic Angiogenesis for Tissue Repair and Regeneration

Currently, there are several therapies designed to induce angiogenesis. Creating new blood vessels leads to tissue repair and a possible reversal of disease symptoms. However, it does not cure the disease. At the moment, there are three major situations for which angiogenic therapies are used: 1) chronic wounds; 2) peripheral arterial disease; and 3) ischemic heart disease. Ischemia is another term for hypoxia. In such conditions, the treatment goal is to stimulate angiogenesis to improve oxygen availability, which will eventually restore the tissue to a healthy state.

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