Angiogenesis is the formation of new blood vessels. This process involves the migration, growth, and differentiation of endothelial cells, which line the inside wall of blood vessels.

The process of angiogenesis is controlled by chemical signals in the body. These signals can stimulate both the repair of damaged blood vessels and the formation of new blood vessels. Other chemical signals, called angiogenesis inhibitors, interfere with blood vessel formation. Normally, the stimulating and inhibiting effects of these chemical signals are balanced so that blood vessels form only when and where they are needed.

Blood vessel formation. Tumor angiogenesis is the growth of new blood vessels that tumors need to grow. This process is caused by the release of chemicals by the tumor and by host cells near the tumor.

Angiogenesis plays a critical role in the growth of cancer because solid tumors need a blood supply if they are to grow beyond a few millimeters in size. Tumors can actually cause this blood supply to form by giving off chemical signals that stimulate angiogenesis. Tumors can also stimulate nearby normal cells to produce angiogenesis signaling molecules.

The resulting new blood vessels “feed” growing tumors with oxygen and nutrients, allowing the tumor to enlarge and the cancer cells to invade nearby tissue, to move throughout the body, and to form new colonies of cancer cells, called metastases.

Because tumors cannot grow beyond a certain size or spread without a blood supply, scientists have developed drugs called angiogenesis inhibitors, which block tumor angiogenesis. The goal of these drugs, also called antiangiogenic agents, is to prevent or slow the growth of cancer by starving it of its needed blood supply.

Angiogenesis inhibitors are unique cancer-fighting agents because they block the growth of blood vessels that support tumor growth rather than blocking the growth of tumor cells themselves.

Angiogenesis inhibitors interfere in several ways with various steps in blood vessel growth. Some are monoclonal antibodies that specifically recognize and bind to VEGF. When VEGF is attached to these drugs, it is unable to activate the VEGF receptor. Other angiogenesis inhibitors bind to VEGF and/or its receptor as well as to other receptors on the surface of endothelial cells or to other proteins in the downstream signaling pathways, blocking their activities. Some angiogenesis inhibitors are immunomodulatory drugs—agents that stimulate or suppress the immune system—that also have antiangiogenic properties.

In some cancers, angiogenesis inhibitors appear to be most effective when combined with additional therapies. Because angiogenesis inhibitors work by slowing or stopping tumor growth without killing cancer cells, they are given over a long period.

The U.S. Food and Drug Administration (FDA) has approved a number of angiogenesis inhibitors to treat cancer. Most of these are targeted therapies that were developed specifically to target VEGF, its receptor, or other specific molecules involved in angiogenesis. Approved angiogenesis inhibitors include:

• Axitinib (Inlyta®)
• Bevacizumab (Avastin®)
• Cabozantinib (Cometriq®)
• Everolimus (Afinitor®)
• Lenalidomide (Revlimid®)
• Lenvatinib mesylate (Lenvima®)
• Pazopanib (Votrient®)
• Ramucirumab (Cyramza®)
• Regorafenib (Stivarga®)
• Sorafenib (Nexavar®)
• Sunitinib (Sutent®)
• Thalidomide (Synovir, Thalomid®)
• Vandetanib (Caprelsa®)
• Ziv-aflibercept (Zaltrap®)

Side effects of treatment with VEGF-targeting angiogenesis inhibitors can include hemorrhage, clots in the arteries (with resultant stroke or heart attack), hypertension, impaired wound healing, reversible posterior leukoencephalopathy syndrome (a brain disorder), and protein in the urine. Gastrointestinal perforation and fistulas also appear to be rare side effects of some angiogenesis inhibitors.

Antiangiogenesis agents that target the VEGF receptor have additional side effects, including fatigue, diarrhea, biochemical hypothyroidism, hand-foot syndrome, cardiac failure, and hair changes.

Angioblasts are stem cells that give rise to blood vessels.

Angiogenesis is the development of new blood vessels from existing vessels.

In a developing embryo,the heart has developed enough by day 21 post-fertilization to begin beating. Circulation patterns are clearly established by the fourth week of embryonic life. It is critical to the survival of the developing human that the circulatory system forms early to supply the growing tissue with nutrients and gases, and to remove waste products. Blood cells and vessel production in structures outside the embryo proper called the yolk sac, chorion, and connecting stalk begin about 15 to 16 days following fertilization. Development of these circulatory elements within the embryo itself begins approximately 2 days later. You will learn more about the formation and function of these early structures when you study the chapter on development. During those first few weeks, blood vessels begin to form from the embryonic mesoderm. The precursor cells are known as hemangioblasts. These in turn differentiate into angioblasts, which give rise to the blood vessels and pluripotent stem cells, which differentiate into the formed elements of blood. (Seek additional content for more detail on fetal development and circulation.) Together, these cells form masses known as blood islands scattered throughout the embryonic disc. Spaces appear on the blood islands that develop into vessel lumens. The endothelial lining of the vessels arise from the angioblasts within these islands. Surrounding mesenchymal cells give rise to the smooth muscle and connective tissue layers of the vessels. While the vessels are developing, the pluripotent stem cells begin to form the blood.

Vascular tubes also develop on the blood islands, and they eventually connect to one another as well as to the developing, tubular heart. Thus, the developmental pattern, rather than beginning from the formation of one central vessel and spreading outward, occurs in many regions simultaneously with vessels later joining together. This angiogenesis—the creation of new blood vessels from existing ones—continues as needed throughout life as we grow and develop.

Blood vessel development often follows the same pattern as nerve development and travels to the same target tissues and organs. This occurs because the many factors directing growth of nerves also stimulate blood vessels to follow a similar pattern. Whether a given vessel develops into an artery or a vein is dependent upon local concentrations of signaling proteins.

As the embryo grows within the mother’s uterus, its requirements for nutrients and gas exchange also grow. The placenta—a circulatory organ unique to pregnancy—develops jointly from the embryo and uterine wall structures to fill this need. Emerging from the placenta is the umbilical vein, which carries oxygen-rich blood from the mother to the fetal inferior vena cava via the ductus venosus to the heart that pumps it into fetal circulation. Two umbilical arteries carry oxygen-depleted fetal blood, including wastes and carbon dioxide, to the placenta. Remnants of the umbilical arteries remain in the adult. (Seek additional content for more information on the role of the placenta in fetal circulation.)

There are three major shunts—alternate paths for blood flow—found in the circulatory system of the fetus. Two of these shunts divert blood from the pulmonary to the systemic circuit, whereas the third connects the umbilical vein to the inferior vena cava. The first two shunts are critical during fetal life, when the lungs are compressed, filled with amniotic fluid, and nonfunctional, and gas exchange is provided by the placenta. These shunts close shortly after birth, however, when the newborn begins to breathe. The third shunt persists a bit longer but becomes nonfunctional once the umbilical cord is severed. The three shunts are as follows (Figure):

The foramen ovale is an opening in the interatrial septum that allows blood to flow from the right atrium to the left atrium. A valve associated with this opening prevents backflow of blood during the fetal period. As the newborn begins to breathe and blood pressure in the atria increases, this shunt closes. The fossa ovalis remains in the interatrial septum after birth, marking the location of the former foramen ovale. The ductus arteriosus is a short, muscular vessel that connects the pulmonary trunk to the aorta. Most of the blood pumped from the right ventricle into the pulmonary trunk is thereby diverted into the aorta. Only enough blood reaches the fetal lungs to maintain the developing lung tissue. When the newborn takes the first breath, pressure within the lungs drops dramatically, and both the lungs and the pulmonary vessels expand. As the amount of oxygen increases, the smooth muscles in the wall of the ductus arteriosus constrict, sealing off the passage. Eventually, the muscular and endothelial components of the ductus arteriosus degenerate, leaving only the connective tissue component of the ligamentum arteriosum. The ductus venosus is a temporary blood vessel that branches from the umbilical vein, allowing much of the freshly oxygenated blood from the placenta—the organ of gas exchange between the mother and fetus—to bypass the fetal liver and go directly to the fetal heart. The ductus venosus closes slowly during the first weeks of infancy and degenerates to become the ligamentum venosum.

Fetal Shunts

The foramen ovale in the interatrial septum allows blood to flow from the right atrium to the left atrium. The ductus arteriosus is a temporary vessel, connecting the aorta to the pulmonary trunk. The ductus venosus links the umbilical vein to the inferior vena cava largely through the liver.

Review

Blood vessels begin to form from the embryonic mesoderm. The precursor hemangioblasts differentiate into angioblasts, which give rise to the blood vessels and pluripotent stem cells that differentiate into the formed elements of the blood. Together, these cells form blood islands scattered throughout the embryo. Extensions known as vascular tubes eventually connect the vascular network. As the embryo grows within the mother’s womb, the placenta develops to supply blood rich in oxygen and nutrients via the umbilical vein and to remove wastes in oxygen-depleted blood via the umbilical arteries. Three major shunts found in the fetus are the foramen ovale and ductus arteriosus, which divert blood from the pulmonary to the systemic circuit, and the ductus venosus, which carries freshly oxygenated blood high in nutrients to the fetal heart.

Vascular Endothelial Growth Factor (VEGF)

A substance made by cells that stimulates new blood vessel formation. Also called vascular endothelial growth factor.

Vascular endothelial growth factor receptor tyrosine kinase inhibitor

A substance that blocks an enzyme needed to form blood vessels. Also called VEGFR tyrosine kinase inhibitor.

Vascular endothelial growth factor trap

A drug used with other drugs to treat colorectal cancer that has spread to other parts of the body and has not gotten better with other chemotherapy. It is also being studied in the treatment of other types of cancer. Vascular endothelial growth factor trap blocks a protein called VEGF, which may prevent the growth of new blood vessels that tumors need to grow. It is a type of antiangiogenesis agent. Also called VEGF Trap, Zaltrap, and ziv-aflibercept.

Vascular endothelial growth factor-antisense oligonucleotide

A substance that has been studied in the treatment of cancer. It binds to the RNA for a protein called vascular endothelial growth factor (VEGF) that stimulates the growth of new blood vessels. Vascular endothelial growth factor-antisense oligonucleotide blocks the cell’s ability to make VEGF, which may kill tumors that need new blood vessels to grow. It is a type of antisense oligonucleotide and a type of gene expression inhibitor. Also called VEGF-AS.

The most common treatment doctors use to slow vision loss from wet AMD is called anti-VEGF injections. These medicines help stop bleeding and leaking from blood vessels in the back of your eye.

When you get this treatment, your doctor will:

• Put numbing medicine in your eye so you won’t feel pain from the injection
• Clean your eye to keep it from getting infected
• Give a shot of the anti-VEGF medicine into your eye with a very small needle

After the treatment, you may need to use antibiotic eye drops to keep your eyes from getting an infection.

Anti-VEGF injections usually only work for a short time, so most people need to get them many times. At first, most people need injections once a month. After that, your doctor will tell you how often you need injections to help stop vision loss from AMD.