Understanding Angiogenisis

Angiogenesis (angio'gen'esis) - the growth of new blood vessels - is an important natural process occurring in the body, both in health and in disease.

The Body's Control of Angiogenesis
Angiogenesis occurs in the healthy body for healing wounds and for restoring blood flow to tissues after injury or insult. In females, angiogenesis also occurs during the monthly reproductive cycle (to rebuild the uterus lining, to mature the egg during ovulation) and during pregnancy (to build the placenta, the circulation between mother and fetus).

The healthy body controls angiogenesis through a series of "on" and "off" switches:

  • The main "on" switches are known as angiogenesis-stimulating growth factors
  • The main "off switches" are known as angiogenesis inhibitors

When angiogenic growth factors are produced in excess of angiogenesis inhibitors, the balance is tipped in favor of blood vessel growth. When inhibitors are present in excess of stimulators, angiogenesis is stopped. The normal, healthy body maintains a perfect balance of angiogenesis modulators.

Excessive angiogenesis:

  • Occurs in diseases such as cancer, diabetic blindness, age-related macular degeneration, rheumatoid arthritis, and psoriasis, and more than 70 other conditions.
  • In these conditions, new blood vessels feed diseased tissues, destroy normal tissues, and in the case of cancer, the new vessels allow tumor cells to escape into the circulation and lodge in other organs (tumor metastases).
  • Excessive angiogenesis occurs when diseased cells produce abnormal amounts of angiogenic growth factors, overwhelming the effects of natural angiogenesis inhibitors.
  • Antiangiogenic therapies, aimed at halting new blood vessel growth, are being developed to treat these conditions.

Insufficient angiogenesis:

  • Occurs in diseases such as coronary artery disease, stroke and delayed wound healing.
  • In these conditions, inadequate blood vessels grow and circulation is not properly restored, leading to the risk of tissue death.
  • Insufficient angiogenesis occurs when the tissue cannot produce adequate amounts of angiogenic growth factors.
  • Therapeutic angiogenesis, aimed at stimulating new blood vessel growth with growth factors, is being developed to treat these conditions.

The Angiogenesis Process

How Do New Blood Vessels Grow?
The process of angiogenesis occurs as an orderly series of events:

  1. Diseased or injured tissues produce and release angiogenic growth factors (proteins) that diffuse into the nearby tissues.
  2. The angiogenic growth factors bind to specific receptors located on the endothelial cells of nearby preexisting blood vessels.
  3. Once growth factors bind to their receptors, the endothelial cells become activated. Signals are sent from the cell's surface to the nucleus. The endothelial cell's machinery begins to produce new molecules including enzymes.
  4. Enzymes dissolve tiny holes in the sheath-like covering (basement membrane) surrounding all existing blood vessels.
  5. The endothelial cells begin to divide (proliferate), and they migrate out through the dissolved holes of the existing vessel towards the diseased tissue (tumor).
  6. Specialized molecules called adhesion molecules, or integrins (vß3, vß5) serve as grappling hooks to help pull the sprouting new blood vessel sprout forward.
  7. Additional enzymes (matrix metalloproteinases) are produced to dissolve the tissue in front of the sprouting vessel tip in order to accommodate it. As the vessel extends, the tissue is remolded around the vessel.
  8. Sprouting endothelial cells roll up to form a blood vessel tube.
  9. Individual blood vessel tubes connect to form blood vessel loops that can circulate blood.
  10. Finally, newly formed blood vessel tubes are stabilized by specialized muscle cells (smooth muscle cells, pericytes) that provide structural support. Blood flow then begins.

Angiogenesis in Disease

In 1994, the Angiogenesis Foundation identified angiogenesis as a "common denominator" in society's most important diseases. Angiogenesis therapies - designed to "turn on" or "turn off" - are revolutionizing medicine by providing a unified approach for treating crippling and life-threatening conditions. Currently, more than 200 biotechnology, genomics, and medical device companies and major pharmaceutical companies are racing to develop new angiogenesis-based medicines.

For a more detailed description of angiogenesis and its importance in cancer research, view the "Understanding Angiogenesis" tutorial, from the National Cancer Institute's "Science Behind the News" series at http://press2.nci.nih.gov/sciencebehind/angiogenesis/angio01.htm.

Angiogenesis in Breast Cancer

Research to date has documented the process of angiogenesis that occurs in the development of breast cancer. All solid breast tumors become clinically relevant once they develop a blood supply. Recent developments in optical imaging technology and image processing make it possible to identify the minute vascular changes associated with a growing cancer in the breast at its earliest stages. Once detected, the changes constitute a unique vascular profile that has the potential to indicate the presence of breast cancer before a cancerous lesion is discernable.

(Photo courtesy of Dr. David Cheresh, Scripps Research Institute.)

Theoretical Tumor Growth Timeline

Facts & Figures

Blood vessels are comprised of cells called 'endothelial cells'. The total surface area covered by these cells in an adult is 1000 m2 - roughly the size of a tennis court.

  • If all the blood vessels in the body were lined up end-to-end, they would form a line that could circle the earth twice.
  • Blood vessel cells do not normally grow in the healthy adult - they are normally inactive, or quiescent.
  • There are more than 19 known angiogenic growth factors.
  • Five of the angiogenic growth factors are being tested in humans for growing new blood vessels to heal wounds, and to restore blood flow to the heart, limbs and brain.
  • The first commercially-available angiogenic growth factor is PDGF-BB (platelet-derived growth factor-BB, Regranex(TM)) used to speed healing in chronic wounds.
  • Angiogenic gene therapy is also being developed as a method to deliver angiogenic growth factors to the heart, limbs and wounds.
  • There are at least 30 known natural angiogenesis inhibitors found in the body.
  • The first angiogenesis inhibitor molecule was discovered in 1975 by Drs. Henry Brem and Judah Folkman during their study of cartilage.
  • Angiogenesis inhibitors have been discovered from natural sources, including: tree bark, fungi, shark muscle and cartilage, sea coral, green tea and herbs (licorice, ginseng, cumin, garlic).
  • In total, more than 300 angiogenesis inhibitors have been discovered to date.
  • As many as 150 million patients in Western nations could benefit from some form of antiangiogenic therapy.
  • At least 300 million patients in Western nations would benefit from some form of angiogenesis-stimulating (pro-angiogenic) therapy.
  • The first successful treatment of an angiogenesis-dependent disease occurred in 1989, when the drug interferon alfa2a, an angiogenesis inhibitor, was used to regress the abnormal blood vessels growing in the lungs of a boy with a benign disease called pulmonary hemangiomatosis.
  • At least 6,500 cancer patients have been treated with some form of experimental antiangiogenic therapy.
  • Some cancer patients have experienced dramatic regression of their tumor from antiangiogenic therapy; others have experienced stabilization of their disease.
  • More than 1,000 patients with heart disease have received some form of experimental angiogenic therapy.
  • The first FDA-approved device to stimulate new blood vessels to grow in diseased hearts is a laser used in a technique called Direct Myocardial Revascularization.
  • The first FDA-approved blood vessel therapy for eye disease is a type of photodynamic therapy called Visudyne (QLT Therapeutics/CibaVision), which has shown effectiveness for treating macular degeneration.
  • The first FDA-approved angiogenesis-stimulating medicine is a wound healing gel called Regranex (recombinant human platelet-derived growth factor-BB, Ortho-McNeil Pharmaceuticals) which was FDA-approved to treat diabetic foot ulcers in December 1997.
  • An estimated $4 billion has been invested in the research and development angiogenesis-based medicines, making this one of the most heavily funded areas of medical research in human history.

DOBI Medical Systems would like to thank Dr. William Li and the Angiogenesis Foundation for providing much of the information presented above. For more information on the Angiogenesis Foundation, please visit www.angio.org.

Investigational Device: Limited by Federal Law to Investigational Use Only. Copyright ©2000-2001 DOBI Medical Systems All Rights Reserved.
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