The term Angiogenesis
was first used by Dr. John Hunter, a British
surgeon in 1787 to describe the growth of new blood vessels in Reindeer antlers
. It occurs in healthly tissue
, where it is used by the body to repair damage
caused by wounds
. In women
it also occurs during the reproductive cycle
, (to rebuild the lining of the uterus
), also during pregnancy
to make the placenta
and (of course!) in the baby
The body naturally produces chemicals which both stimulate
this process, and disease can occur when the balance between growth and inhibition
Excessive angiogenisis can occur when diseased
cells, (such as cancer
cells) release angiogenic growth factors, which tips the balance in favour of rapid new blood vessel production. These new blood vessels can rip though healthy organs
and tissues, impairing their function. Also in cancerous tissues this influx of new blood not only helps a tumour
grow, but provides it with the means to sow
the seeds of new tumours, by spreading cancerous cells throughout the body. (Metastases
More than 70 other conditions have been linked to excessive angiogenis, such as psoriasis
, diabetic blindness
and diabetic ulcers
, rheumatoid arthritis
, even the degeneration
of our eyes
as we age
If you can't produce enough angiogenetic growth factors, wound healing
may be greatly slowed, which can cause necrosis
of the affected area. Coronary heart disease
have also been linked to insuffiecent AGF.
Needless to say, these are important
targets for drug
companies, and a huge amount of ongoing research is targeting angiogenesis. Indeed in 1999 Dr. Richard Klausner, the director of the USA National Cancer Institute
targeted angiogenenic therapies as a national
priority. It's easy to see why, cancer is one of the biggest killers, and trials have shown regression
or even complete remision
of cancers in many patients.
The Process of Angiogenesis
- Angeniogenic growth factor production. (AGF)Damaged (or diseased) tissues release angiogenic growth factors, that diffuse out into surrounding tissue.
- Receptor binding. Once the AGF's reach existing blood vessels, they bind to receptors on endothelial cells
- Endothelial cell activation. The binding of the AGF stimulates the cell to produce enzymes. These enzymes dissolve holes into the porous basement membrane that surrounds the blood vessels, until the holes are large enough for cells to pass through.
- Endothelial cell proliferation. The EC's undergo rapid cell division and diffuse out into the extra cellular matrix (ECM).
- Directional migration. The damaged tissues leak chemicals that allow the migrating cells to move toward the affected area, by moving from low to high concentration. Also integrin (fibrin) molecules are released from the affected area, which also provide a path, as well as supporting the nascent bloodvessel.
- ECM remodelling. A path is cleared through the matrix by metalloproteinases(MMP's), these enzymes literally dissolve the tissue in front of the advancing endothelial cells. Some of the breakdown products of the ECM can in fact promote the angiogenic response, helping the growth of the tip of the new blood vessel.
- Tube formation. Once the process is mature enough, the endothelial cells roll up to form a tube, strong enough to carry blood vessels.
- Loop formation. During this stage the loops needed to carry blood to and from the damaged tissue are formed.
- Vascular stabilisation. Finally the vessel is made strong enough to cope with blood flow by smooth muscle cells providing structural support. Only then does blood flow begin.
treatments can work inhibiting any of the above stages.