Sprouting angiogenesis was the first identified form of angiogenesis. It occurs in several well-characterized stages.
First, biological signals known as angiogenic growth factors activate receptors present on endothelial cells present in pre-existing blood vessels.
Second, the activated endothelial cells begin to release enzymes called proteases that degrade the basement membrane in order to allow endothelial cells to escape from the original (parent) vessel walls.
The endothelial cells then proliferate into the surrounding matrix and form solid sprouts connecting neighboring vessels.
As sprouts extend toward the source of the angiogenic stimulus, endothelial cells migrate in tandem, using adhesion molecules, the equivalent of cellular grappling hooks, called integrins. These sprouts then form loops to become a full-fledged vessel lumen as cells migrate to the site of angiogenesis.
Sprouting occurs at a rate of several millimeters per day, and enables new vessels to grow across gaps in the vasculature. It is markedly different from splitting angiogenesis, however, because it forms entirely new vessels as opposed to splitting existing vessels.
''Intussusception'', also known as splitting angiogenesis, was first observed in neonatal rats. In this type of vessel formation, the capillary wall extends into the lumen to split a single vessel in two.
There are four phases of intussusceptive angiogenesis.
First, the two opposing capillary walls establish a zone of contact.
Second, the endothelial cell junctions are reorganized and the vessel bilayer is perforated to allow growth factors and cells to penetrate into the lumen.
Third, a core is formed between the two new vessels at the zone of contact that is filled with pericytes and myofibroblasts. These cells begin laying collagen fibers into the core to provide an extracellular matrix for growth of the vessel lumen.
Finally, the core is fleshed out with no alterations to the basic structure.
Intussusception is important because it is a reorganization of existing cells. It allows a vast increase in the number of capillaries without a corresponding increase in the number of endothelial cells. This is especially important in embryonic development as there are not enough resources to create a rich microvasculature with new cells every time a new vessel develops.
Modern terminology of angiogenesis
Besides the differentiation between “Sprouting angiogenesis” and “Intussusceptive angiogenesis” there exists the today more common differentiation between the following types of angiogenesis:
Vasculogenesis – Formation of vascular structures from circulating or tissue-resident endothelial stem cells (angioblasts), which proliferate into ''de novo'' endothelial cells. This form particularly relates to the embryonal development of the vascular system.
Angiogenesis – Formation of thin-walled endothelium-lined structures with muscular smooth muscle wall and pericytes (fibrocytes). This form plays an important role during the adult life span, also as "repair mechanism" of damaged tissues.
Arteriogenesis – Formation of medium-sized blood vessels possessing tunica media plus adventitia.
Because it turned out that even this differentiation is not a sharp one, today quite often the term “Angiogenesis” is used summarizing all different types and modifications of arterial vessel growth.
- Rubanyi, G.M. (Ed): Angiogenesis in health and disease. M.Dekker, Inc., New York – Basel, 2000
- Raizada, M.K., Paton, J.F.R., Kasparov, S., Katovich, M.J. (Eds): Cardiovascular genomics. Humana Press, Totowa, N.J., 2005
- Kornowski, R., Epstein, S.E., Leon, M.B.(Eds.): Handbook of myocardial revascularization and angiogenesis. Martin Dunitz Ltd., London, 2000
- Stegmann, T.J.: New Vessels for the Heart. Angiogenesis as New Treatment for Coronary Heart Disease: The Story of its Discovery and Development. Henderson, Nevada: CardioVascular BioTherapeutics Inc., 2004
- Laham, R.J., Baim, D.S.: Angiogenesis and direct myocardial revascularization. Humana Press, Totowa, NJ, 2005
Angiogenesis as a therapeutic target
Angiogenesis may be a target for combatting diseases characterized by either poor vascularisation or abnormal vasculature. Application of specific compounds that may inhibit or induce the creation of new blood vessels in the body may help combat such diseases.
The presence of blood vessels where there should be none may affect the mechanical properties of a tissue, increasing the likelihood of failure.
The absence of blood vessels in a repairing or otherwise metabolically active tissue may inhibit repair or other essential functions.
Several diseases, such as ischemic chronic wounds, are the result of failure or insufficient blood vessel formation and may be treated by a local expansion of blood vessels, thus bringing new nutrients to the site, facilitating repair.
Other diseases, such as age-related macular degeneration, may be created by a local expansion of blood vessels, interfering with normal physiological processes.
The modern clinical application of the principle of angiogenesis can be divided into two main areas: anti-angiogenic therapies, which angiognic research began with, and pro-angiogenic therapies.
Whereas anti-angiogenic therapies are being employed to fight cancer and malignancies, which require an abundance of oxygen and nutrients to proliferate, pro-angiogenic therapies are being explored as options to treat cardiovascular diseases, the number one cause of death in the Western world.
One of the first applications of pro-angiogenic methods in humans was a German trial using fibroblast growth factor 1 (FGF-1) for the treatment of coronary artery disease.
Clinical research in therapeutic angiogenesis is ongoing for a variety of atherosclerotic diseases, like coronary heart disease, peripheral arterial disease, wound healing disorders, etc..
Also, regarding the mechanism of action, pro-angiogenic methods can be differentiated into three main categories: gene-therapy, targeting genes of interest for ampliification or inhibition; protein-therapy, which primarily manipulates angiogenic growth factors like FGF-1 or vascular endothelial growth factor, VEGF; and cell-based therapies, which involve the implantation of specific cell types.
There are still serious, unsolved problems related to gene therapy. Difficulties include effective integration of the therapeutic genes into the genome of target cells, reducing the risk of an undesired immune response, potential toxicity, immunogenicity, inflammatory responses, and oncogenesis related to the viral vectors used in implanting genes and the sheer complexity of the genetic basis of angiogenesis.
The most commonly-occurring disorders in humans such as heart disease, high blood pressure, diabetes, Alzheimer’s disease are most likely caused by the combined effects of variations in many genes, and, thus, injecting a single gene may not be significantly beneficial in such diseases.
In contrast, pro-angiogenic protein therapy uses well-defined, precisely-structured proteins, with previously-defined optimal doses of the individual protein for disease states, and with well-known biological effects.
On the other hand, an obstacle of protein therapy is the mode of delivery. Oral, intravenous, intra-arterial, or intramuscular routes of protein administration are not always as effective, as the therapeutic protein may be metabolized or cleared before it can enter the target tissue.
Cell-based pro-angiogenic therapies are still early stages of research, with many open questions regarding best cell types and dosages to use.
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