Angiogenesis is a fundamental biological process defined as the creation of new blood vessels from a pre-existing vascular network. This process is constantly regulated, allowing the body to adapt its circulatory system to changing demands for oxygen and nutrients. The growth of capillaries, the body’s smallest blood vessels, is a tightly controlled mechanism that influences tissue growth, repair, and metabolism. Understanding the control mechanisms of angiogenesis is a major focus because its dysregulation is implicated in a wide array of human diseases.
How New Blood Vessels Form
The formation of new blood vessels is a coordinated sequence of events initiated when tissues experience low oxygen levels, known as hypoxia. This oxygen deprivation signals local cells to release chemical messengers, most notably Vascular Endothelial Growth Factor (VEGF). VEGF is the primary pro-angiogenic factor that binds to specific receptors on endothelial cells, which line the inside of existing blood vessels.
Once activated by VEGF, endothelial cells change their behavior by increasing the permeability of the existing vessel and causing dilation. These activated cells then secrete enzymes, such as matrix metalloproteinases (MMPs), which break down the basement membrane. This degradation clears a path for the endothelial cells to escape the parent vessel and migrate into the surrounding tissue.
The migrating endothelial cells at the leading edge are termed “tip cells” because they follow the chemical gradient of VEGF toward the oxygen-starved area. Behind the tip cells, “stalk cells” proliferate and form a hollow tube, a process called lumen formation, extending the new vessel. Finally, the newly formed vessel is stabilized as pericytes, cells that wrap around the capillaries, are recruited to the site, providing structural integrity and completing the new blood supply.
Role in Healthy Body Functions
While often discussed in the context of disease, new blood vessel growth is a necessary function in healthy physiology. During embryonic development, angiogenesis constructs the entire vascular tree, required for the growth of all fetal organs and tissues. Without this initial formation, the growing organism could not receive the oxygen and nutrients.
In adults, the mechanism is primarily used for temporary or cyclic demands for increased blood flow. When tissue is injured, angiogenesis is activated to support wound healing by restoring circulation, delivering immune cells, and supplying components for tissue repair. The process shuts down once the tissue has healed, demonstrating its tightly controlled nature.
Angiogenesis also plays a regular, cyclical role in the female reproductive system. The growth and shedding of the uterine lining, or endometrium, during the menstrual cycle relies on the rapid creation and regression of blood vessels. Extensive, temporary vascular growth is also demanded during the formation of the corpus luteum in the ovary and the development of the placenta during pregnancy.
Disease Driven by Vascular Growth
When the balance between pro-angiogenic factors like VEGF and anti-angiogenic inhibitors is disrupted, excessive vessel growth can drive various pathologies. The most widely studied example is cancer; solid tumors cannot grow beyond a few millimeters without co-opting the host’s blood supply. Tumors release massive amounts of VEGF, inducing the body to build a vascular network directly into the cancerous mass.
This tumor-induced vasculature feeds the malignant cells with the oxygen and nutrients required for growth. The newly formed, disorganized, and leaky tumor vessels provide a pathway for cancer cells to enter the bloodstream and travel to distant sites (metastasis). The tumor effectively hijacks a normal repair mechanism to ensure its own survival and spread.
Abnormal vascular growth is the underlying cause of several serious eye conditions. In wet Age-related Macular Degeneration (AMD), vessels grow abnormally beneath the retina, the light-sensing tissue at the back of the eye. These fragile vessels are prone to leaking blood and fluid, which damages the macula and leads to rapid vision loss.
Diabetic retinopathy is a complication of diabetes where high blood sugar levels damage existing vessels, triggering a hypoxic response that leads to uncontrolled, abnormal new vessel growth in the retina. These pathological vessels, which are weak and leaky, can cause hemorrhages, scarring, and retinal detachment, resulting in blindness. Chronic inflammatory conditions like rheumatoid arthritis also involve excessive blood vessel formation, which helps sustain the inflammation in affected joints.
Targeting Angiogenesis in Medicine
The discovery of angiogenesis as a disease driver opened a new avenue for therapeutic intervention focused on manipulating the vascular supply. The dominant strategy, anti-angiogenic therapy, aims to block excessive vessel formation by targeting the VEGF signaling pathway. These treatments are designed to starve tumors or halt pathological vessel leakage in the eye.
For neovascular AMD, anti-VEGF drugs are injected directly into the eye to neutralize excess VEGF, reducing leakage and preventing further vision loss. In oncology, VEGF inhibitors like bevacizumab treat various solid tumors, including certain colorectal, lung, and kidney cancers. The goal is often to normalize the tumor vasculature, making it less leaky and more responsive to chemotherapy, rather than eliminating it completely.
Conversely, pro-angiogenic therapy is a more experimental approach that focuses on stimulating new vessel growth where blood supply is insufficient. This strategy is being investigated for treating ischemic diseases, such as chronic non-healing wounds or conditions caused by arterial blockages. For instance, delivering growth factors to heart muscle after a heart attack could encourage collateral circulation to bypass damaged areas and restore blood flow.
While anti-angiogenic therapies have revolutionized treatment, researchers continually work on new agents that target other factors involved in vessel stabilization, such as the Platelet-Derived Growth Factor (PDGF) pathway. By exploring both sides of the angiogenic balance—inhibition where growth is harmful and stimulation where it is lacking—medicine continues to refine its ability to control this fundamental biological process.