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
- The main "off switches" are known as angiogenesis
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.
- 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.
- 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
- 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
The Angiogenesis Process
How Do New Blood Vessels Grow?
The process of angiogenesis occurs as an orderly series of events:
- Diseased or injured tissues produce and release angiogenic
growth factors (proteins) that diffuse into the nearby tissues.
- The angiogenic growth factors bind to specific receptors
located on the endothelial cells of nearby preexisting blood
- 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.
- Enzymes dissolve tiny holes in the sheath-like covering
(basement membrane) surrounding all existing blood vessels.
- The endothelial cells begin to divide (proliferate), and
they migrate out through the dissolved holes of the existing
vessel towards the diseased tissue (tumor).
- Specialized molecules called adhesion molecules, or integrins
vß5) serve as grappling hooks to help pull the sprouting
new blood vessel sprout forward.
- 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.
- Sprouting endothelial cells roll up to form a blood vessel
- Individual blood vessel tubes connect to form blood vessel
loops that can circulate blood.
- 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
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
- 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
- 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
- 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
- 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.
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