Angiogenesis

What is Angiogenesis?

Angiogenesis refers to the process of formation of new blood vessels from existing blood vessels and is a critical component of healing and reproduction. It takes place throughout life, beginning in the womb.

Angiogenesis is a highly regulated process through a fine balance of angiogenesis promoting and inhibitory factors. Oxygen plays a key role in the regulation of angiogenesis. When the balance is disturbed, the result is either or too much or too little angiogenesis leading to several diseases including cancer, cardiovascular disease, stroke, skin diseases, age-related blindness, diabetic ulcers, and several others.

History of Angiogenesis

The first recorded scientific insights into the field of angiogenesis were given by the Scottish anatomist and surgeon Sir John Hunter way back in 1794. His observations suggested that the vascularity of any tissue is proportional to its metabolic requirements, and this relation is maintained both in health and disease.

In the modern era, the importance of angiogenesis in the growth and spread of cancer was put forth by Judah Folkman in 1971, leading to a profusion of research in the development of angiogenesis inhibitors for the treatment of cancer in the last four decades.

What are the Steps involved in Angiogenesis?

Angiogenesis is a multistep process that includes the following:

1. Activation of the endothelial cells lining the existing blood vessels by angiogenesis promoting factors such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF)
2. Dissolution of the capillary lining by extracellular matrix metalloproteinases
3. Creation of branch points in the vessel wall
4. Arrival of endothelial cells at the site of blood vessel formation
5. Reorganization of these endothelial cells to form tubes (blood vessels) with a central lumen
6. Interconnection of the newly formed tubules to form a vascular network

Growth factors that stimulate angiogenesis called angiogenic growth factors include basic Fibroblast Growth Factor (bFGF), Granulocyte Colony-Stimulating Factor (G-CSF), Vascular Endothelial Growth Factor (VEGF), Transforming Growth Factors alpha and beta (TGF-α and TGF-β), platelet derived growth factor (PDGF) and Interleukin-8 (IL-8).

Natural angiogenic inhibitors, molecules that prevent angiogenesis, include endostatin, angiostatin, interleukin-12 (IL-12), retinoids and interferons (alpha, beta and gamma).

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What are the Types of Angiogenesis?

The two types of angiogenesis are sprouting and intussusceptive or splitting angiogenesis.

Sprouting angiogenesis

This was the type first described and occurs when new blood vessels sprout or bud from existing blood vessels by the steps outlined in the above paragraph. Sprouting angiogenesis is initiated in tissues when oxygen sensors detect a low level of oxygen (hypoxia), and the process of angiogenesis begins to satisfy the metabolic requirements of the tissue.

Intussusceptive Angiogenesis

Intussusceptive angiogenesis is also called splitting angiogenesis since the capillary wall protrudes into the lumen causing a single vessel to split in two. This form of angiogenesis is believed to be quicker and more efficient in comparison to sprouting angiogenesis because it only requires reorganization of existing endothelial cells and does not need new endothelial cells to migrate to the site.

Intussusceptive angiogenesis occurs throughout life but has been shown to play a critical role in blood vessel formation in embryos where the growth occurs at a fast rate and resources are limited. It is however important to note that, intussusceptive angiogenesis occurs only where capillaries already exist.

How Does Angiogenesis Influence Cancer?

Cancer refers to an abnormal new growth characterized by rapid and uncontrolled proliferation of cells that can spread to other sites. These fast growing tumors need a dedicated blood supply, to supply oxygen and other essential nutrients they require in order to grow beyond a certain size.

Angiogenesis is believed to play an important role both in tumor growth as well as metastasis or distant spread.

Tumor cells stimulate blood vessel growth (angiogenesis) by secreting various growth factors (e.g. VEGF), allowing for tumor expansion and growth. The tumor cells may also stop producing the anti-VEGF enzyme protein kinase G (PKG),thus further promoting the growth of blood vessels. Unlike normal blood vessels, tumor blood vessels are dilated with an irregular shape. Some experts believe that angiogenesis only serves as a waste pathway, to remove the biological end products released by rapidly dividing cancer cells.

Angiogenesis is also necessary for the spread of cancer cells. These cells are carried by the newly formed blood vessels to a distant site, where they can implant and initiate the growth of a secondary tumor (away from the primary). The secondary tumor will also require angiogenesis for its growth and expansion and to remove the metabolic waste products of its rapidly dividing cells.

Research now suggests the blood vessels in solid tumors may, in fact, be mixed or mosaic vessels, composed of tumor cells and endothelial cells. This allows for the shedding of tumor cells into the vessel lumen, possibly contributing to the appearance of circulating tumor cells in the peripheral blood of patients with malignancies.

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Angiogenesis in Cancers and Disease

In addition to cancer, angiogenesis has been shown to be a key component in several diseases and the list continues to grow.

Below is a list of diseases associated with abnormal angiogenesis, both excessive as well as insufficient blood vessel formation.

Excessive angiogenesis

Organ	Disease
Fat tissue	Obesity
Blood vessels	Vascular formations, atherosclerosis
Multiple organs	Cancer, infections, autoimmune diseases
Eye	Diabetic retinopathy, retinopathy of prematurity
Respiratory system	Primary pulmonary hypertension, asthma, nasal polyps
Intestines	Inflammatory bowel disease
Skin	Psoriasis, warts, pyogenic granuloma
Reproductive system	Endometriosis, ovarian cysts
Musculoskeletal system	Arthritis, synovitis, osteomyelitis

Insufficient angiogenesis

Organ	Disease
Nervous system	Alzheimer’s disease
Skin	Hair loss
Bone	Osteoporosis
Kidney	Age related nephropathy
Lung	Neonatal respiratory distress
Reproductive system	Preeclampsia

Angiogenesis-Based Medicine

Angiogenesis-based medicine targets the angiogenic processes that cause disease and aims to restore the normal homeostasis. It is a wide-ranging approach to fight diseases by using new medical treatments that either inhibit or stimulate angiogenesis. With the use of these drugs, doctors can prolong the lives of cancer patients, prevent limb amputations, reverse vision loss, and improve general health.

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Tumor Angiogenesis

Anti-angiogenic treatments cut off the blood supply of the tumor starving it of oxygen and other essential nutrients.

Antiangiogenic drugs are now approved and available to treat several cancers such as those of the colon, lung, breast, liver, brain, kidney, ovaries, and thyroid, as well as multiple myeloma, bone cancers, gastrointestinal stromal tumors, and soft tissue sarcoma.

• The first angiogenic inhibitor to be used to slow cancer growth and progression was Bevacizumab. It is used in glioblastoma, metastatic colorectal cancer, metastatic kidney cancer, and non-small cell lung cancers.
• Sorafenib is approved for liver cancer and kidney cancer, Pazopanib for kidney cancer, and Sunitinib and Everolimus for both kidney cancer and neuroendocrine tumors.
• Some older drugs such as Thalidomide, Suramin and Cannabinoids have been rediscovered as angiogenesis inhibitors, as well. These have the potential to treat angiogenesis-dependent conditions.

• Some dietary foods have also been shown to have mild anti-angiogenic properties. These include soy products, green tea, red wine, liquorice, Reishi and Maitake mushrooms and black raspberry.

Side effects of Angiogenesis Inhibitors

The side effects of anti-angiogenic drugs include the following:

• Bleeding – seen most commonly with Bevacizumab. The exact mechanism is not clear
• Increased blood pressure
• Hand foot syndrome – painful thickened areas on the skin with blisters on the palms and soles
• Dry and itchy skin
• Fatigue
• Low blood counts – anemia, leucopenia and thrombocytopenia
• Diarrhea
• Impaired wound healing
• Rarely intestinal perforation

It is possible that some of the side effects of angiogenic inhibitors are still not known. With increasing use of these drugs, more knowledge will be gained on the other side effects as well.

Therapeutic Angiogenesis

Therapeutic angiogenesis stimulates new vessel formation where it is lacking but necessary. It is used to reinforce the blood supply to chronic wounds and promote healing, and helps to prevent avoidable amputations. Studies suggest that this approach can also be used to save limbs with impaired circulation, and even hearts with poor blood supply. Therapeutic angiogenesis could also help to regenerate damaged or destroyed tissues such as with nerves and brain tissue that were previously considered impossible.

One novel agent that is being used in therapeutic angiogenesis is Becaplermin, which enhances angiogenesis. It has been approved as a local application for diabetic foot ulcers to improve lower limb circulation.