Promoting the growth of new blood vessels through therapeutic angiogenesis may be accomplished through the use of one of the following:

The first strategy is the use of one of the body’s natural growth factors (angiogens). Growth factors are hormones that produce enormous changes throughout the developmental process from the moment of conception, through puberty, to adulthood. Among the changes caused by growth factors is the formation of new blood vessels.

Specific growth factors that are being investigated for their angiogenic effects are basic fibroblast growth factor (bFGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). Of these, FGF and VEGF have been studied the most widely.

Lab studies are showing that growth factors yield positive results when the tissue is continuously exposed to the growth factor for a period of more than a month. As a result, researchers are experimenting with delivery methods, including gene therapy and protein delivery, or direct injection of the growth factor(s). Each appears to have advantages. For example, delivery by protein allows for more precise dosing and avoids the potential problem of introducing foreign DNA into the body. However, proteins tend to have a short half-life, meaning that multiple doses may be necessary. On the other hand, gene therapy allows for long-term production of the growth factor at the target site, requiring only one dose.

To understand gene therapy, and how it is used to delivery growth factors, it is necessary to understand how genes work. In the center of every human cell are 46 chromosomes. Each chromosome contains long, tightly wound strands of DNA (deoxyribonucleic acid), which carry the genetic blueprint for how the human body is constructed and maintained. The DNA blueprint for the body is written in a language that scientists are learning to read. They have identified segments of DNA that occupy a specific location on the chromosome and have specific effects on the body (e.g., manufacturing a protein). These DNA segments are called genes, the basic units of heredity.

In traditional gene therapy, genes that stimulate the production of growth factor are coded into a vector, which is a piece of genetic material from another source (e.g., a virus). This genetic material is introduced into the target tissues, which "turns on" the native genes and stimulates them to produce the coded growth factors. In addition to viral vectors, researchers are also studying nonviral vectors, such as plasmid DNA and liposomal complexes.

At this point, research into growth factors is still highly experimental and the results in human subjects have been somewhat contradictory. Currently, growth factor-derived therapy is reserved for patients who have not responded to conventional therapies, such as bypass surgery or balloon angioplasty.

One area of gene therapy that has received significant attention is the use of stem cells. In this case, genes are not used as a delivery system. Rather, scientists attempt to implant immature stem cells into damaged tissue, hoping that the stem cells will grow (or differentiate) into mature heart muscle or artery cells. This is possible because the immature stem cells have the ability to develop into a variety of mature cells, such as red or white blood cells, platelets, etc.

In various studies, physicians have attempted to transplant a patient’s own stem cells from their bone marrow into the heart after a heart attack. The hope is that these immature bone marrow stem cells will mature into new cardiac muscle to replace the damaged muscle. Results from these trials, however, have been mixed. In some studies, the stem cells failed to mature into new cardiac muscle, while others have shown some improvement.

For heart failure patients, bone marrow cells have been injected into the heart’s left ventricle. Bone marrow cells are seen to enhance the formation of blood vessels and rebuilding of muscle. Early results have been promising, with some study patients responding so well that they were taken off waiting lists for heart transplantation. Other researchers are seeing that bone marrow-derived stem cells implanted into the leg can impact against peripheral arterial disease.

The second strategy involves the use of chemicals that stimulate the production of growth factors. One example is hypoxia-inducible factor 1 (HIF-1), which is a naturally occurring chemical that is produced when the heart experiences a lack of oxygen (hypoxia) during cardiac ischemia. HIF-1 stimulates the production of the growth factor VEGF, which stimulates the growth of new blood vessels (collaterals) to the heart. Because production of HIF-1 appears to be a natural reaction of the body, researchers have been studying its use as a medical treatment.

The third strategy for promoting the growth of collateral blood vessels is the use of medications that mimic the effects of growth factors. For example, one animal study compared the angiogenic effects of a growth factor (VEGF) and a certain drug used to treat high blood pressure. Although the medication was not as effective as the growth factor, it still yielded a significant result. Further research is needed to understand how this medication was able to stimulate angiogenesis and what other medications might be able to do the same thing.

The fourth strategy for promoting angiogenesis is a procedure called transmyocardial revascularization (TMR). In this procedure, a laser beam is used to form up to 40 small holes, or channels, in the heart muscle (myocardium) of the left ventricle. The laser may be introduced to the body either through surgery or via a catheter that is fed through the femoral artery in the groin and all the way up to the heart. The exact mechanism by which TMR increases blood blow is not completely understood. It may function by stimulating new blood cells, or it may work by destroying nerve cells, thus stopping the patient from feeling any pain. This procedure is approved by the U.S. Food and Drug Administration for patients with severe angina who lack other treatment options. So far, in large, clinical trials, it has shown short-term benefit, but there are no long-term studies to see how TMR fares over the course of many years. A randomized trial of percutaneous catheter directed TMR from the femoral artery showed no benefit. TMR is still used at the time of CABG if some areas of the heart do not have adequate arteries for bypass.

Therapeutic angiogenesis is difficult to clinically evaluate, because a patient who makes certain lifestyle changes (specifically exercise) and regularly takes medications can stimulate the growth of collaterals without additional therapy. Clinical testing has found it challenging to differentiate between the positive effects of therapeutic angiogenesis and the positive effects experienced by those individuals in a controlled placebo group.