Thursday, December 20, 2007

Applications of Angiogenesis

Types of angiogenesis

Sprouting angiogenesis

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 venular 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 [1].

Intussusceptive angiogenesis

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/without 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

Therapeutic angiogenesis

Therapeutic angiogenesis is the application of specific compounds which may inhibit or induce the creation of new blood vessels in the body in order to combat disease. 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 retard repair or some other function. Several diseases (eg. 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 “angiogenesis” can be divided into two main areas: 1. Anti-angiogenic therapies (historically, research started with); 2. Pro-angiogenic therapies. Whereas anti-angiogenic therapies are trying to fight cancer and malignancies[2][3] (because tumors, in general, are nutrition- and oxygen-dependent, thus being in need of adequate blood supply), the pro-angiogenic therapies are becoming more and more important in the search of new treatment options for cardiovascular diseases (the number one cause of death in the Western world). One of the world-wide first applications of usage of pro-angiogenic methods in humans was a German trial using fibroblast growth factor 1 (FGF-1) for the treatment of coronary artery disease[4][5][6]. Today, clinical research is ongoing in various clinical trials to promote therapeutic angiogenesis for a variety of atherosclerotic diseases, like coronary heart disease, peripheral arterial disease, wound healing disorders, etc.[7].

Also, regarding the “mode of action”, pro-angiogenic methods can be differentiated into three main categories: 1. Gene-therapy; 2. Protein-therapy (using angiogenic growth factors like FGF-1 or vascular endothelial growth factor, VEGF); 3. Cell-based therapies. There are still serious, unsolved problems related to gene therapy including: 1. Difficulty integrating the therapeutic DNA (gene) into the genome of target cells; 2. Risk of an undesired immune response; 3 Potential toxicity, immunogenicity, inflammatory responses and oncogenesis related to the viral vectors; and 4. 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 will not be beneficial in these 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 the protein’s administration are not always as effective as desired; the therapeutic protein can be metabolized or cleared before it can enter the target tissue. Cell-based pro-angiogenic therapies are still in an early stage of research – with many open questions regarding best cell types and dosages to use.


  1. ^ Burri, PH (2004). "Intussusceptive angiogenesis: its emergence, its characteristics, and its significance.". Dev Dyn. 231 (3): 474-88.
  2. ^ Folkman, J, Klagsbrun, M: Angiogenetic factors. Science 235: 442-447, 1987
  3. ^ Folkman J. Fighting cancer by attacking its blood supply. Sci Am. 275:150 –154, 1996
  4. ^ Schumacher, B., Pecher, P., von Specht, B.U., Stegmann, T.J.: Induction of neoangiogenesis in ischemic myocardium by human growth factors. Circulation 97: 645-650, 1998
  5. ^ Folkman, J.: Angiogenic therapy of the heart. Circulation 97: 628-629, 1998
  6. ^ Stegmann, T.J.: A human growth factor in the induction of neoangiogenesis. Exp.Opin.Invest.Drugs 7: 2011-2015, 1998
  7. ^ Wagoner, L.E., Merrill, W., Jacobs, J., Conway, G., Boehmer, J., Thomas, K., Stegmann, T.J.: Angiogenesis Protein Therapy With Human Fibroblast Growth Factor (FGF-1): Results Of A Phase I Open Label, Dose Escalation Study In Subjects With CAD Not Eligible For PCI Or CABG. Circulation 116: 443, 2007

Mechanical stimulation

Mechanical stimulation of angiogenesis is not well characterized. There is a significant amount of controversy with regard to shear stress acting on capillaries to cause angiogenesis, although current knowledge suggests that increased muscle contractions may increase angiogenesis[8]. This may be due to an increase in the production of nitric oxide during exercise.

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