Angiogenesis is the biological process through which the body grows new blood vessels from an existing network. It is distinct from vasculogenesis, the initial formation of vessels during embryonic development. Sprouting angiogenesis is the most common form in adults, where endothelial cells form new capillary branches that invade surrounding tissue. This growth expands the vascular supply into areas requiring oxygen and nutrient delivery. It differs from intussusceptive angiogenesis, which splits existing vessels rather than growing new sprouts.
The Cellular Steps of New Vessel Growth
The formation of a new vessel begins when surrounding tissue experiences low oxygen levels, known as hypoxia, triggering signaling molecules. The primary signal is Vascular Endothelial Growth Factor (VEGF-A), which binds to receptors on endothelial cells lining the parent vessel. This signal activates the endothelial cells, causing them to secrete proteases that locally degrade the basement membrane and the extracellular matrix (ECM). This degradation creates a path for the new vessel to emerge and penetrate the tissue.
A specialized “tip cell” leads the new sprout through the degraded matrix. The tip cell does not proliferate but is highly migratory, extending long, slender protrusions called filopodia that sense the chemical gradient of VEGF to guide the sprout toward the stimulus. Following the non-proliferative tip cell are “stalk cells,” responsible for the elongation of the new vessel.
Stalk cells rapidly proliferate and form a hollow tube, or lumen. The balance between the migratory tip cell and the proliferative stalk cells is tightly regulated by a signaling pathway involving Delta-like 4 (Dll4) on the tip cell and the Notch receptor on the stalk cells. Once the new sprout fuses with another vessel, endothelial cells recruit supporting cells called pericytes. Pericytes wrap around the new capillary, depositing a new basement membrane to stabilize the structure and allow for functional blood flow.
Natural Functions in Health and Development
Sprouting angiogenesis is a tightly controlled mechanism that serves multiple beneficial purposes. In the earliest stages of life, it plays a role in the maturation of the primitive vascular network established during embryonic development. This ensures that all organs receive the necessary blood supply as the embryo grows rapidly.
In adult physiology, the process is activated temporarily for repair and regeneration, such as during wound healing. When tissue is damaged, new capillaries must grow quickly into the wound bed to deliver oxygen, immune cells, and nutrients required for repair. The transient nature of this process is evident in the female reproductive cycle, where the lining of the uterus (the endometrium) is built up and shed each month.
Capillaries are quickly formed in the endometrium to support its growth, and then they regress when the tissue is broken down. This demonstrates a balanced cycle of vessel formation and regression necessary for tissue function and adaptation to metabolic demands. Skeletal muscle increases its capillary density through angiogenesis in response to sustained exercise to improve oxygen delivery.
Angiogenesis as a Driver of Disease
While sprouting angiogenesis is beneficial for growth and repair, its dysregulation underlies the progression of numerous diseases. The most widely recognized pathological role is cancer, where solid tumors cannot grow beyond one to two millimeters without their own dedicated blood supply. Tumors hijack the angiogenic mechanism by releasing excessive pro-angiogenic factors, most notably VEGF, to force nearby vessels to sprout toward them.
Tumor-induced angiogenesis provides cancer cells with the oxygen and nutrients needed for sustained proliferation and growth. The newly formed, disorganized, and leaky tumor vessels act as conduits, facilitating the spread of malignant cells throughout the body (metastasis). These vessels are structurally abnormal and asymmetrical, distinguishing them from healthy, stable vessels.
Pathological angiogenesis also contributes to vision loss in conditions like diabetic retinopathy and age-related macular degeneration. In diabetic retinopathy, high blood sugar damages retinal vessels, leading to oxygen starvation. In response to hypoxia, the retina releases VEGF, triggering the growth of fragile, abnormal new vessels that bleed easily and cause scarring, ultimately leading to blindness. Chronic inflammatory diseases involve sustained, abnormal angiogenesis, where new vessels perpetuate the inflammatory state.
Therapeutic Manipulation of Sprouting
The recognition that abnormal sprouting angiogenesis drives many diseases has led to therapies aimed at modulating this process. Anti-angiogenic therapies are designed to starve tumors or prevent destructive new vessel growth in the eye. These treatments often work by directly blocking VEGF or its receptors, inhibiting the key signal required to initiate sprouting.
Anti-angiogenic agents are widely used in treating various cancers to slow tumor growth by cutting off their blood supply. They are also a standard treatment for wet age-related macular degeneration and diabetic retinopathy, where blocking VEGF prevents the formation and leakage of abnormal vessels. The goal is to shift the balance away from vessel formation and toward vessel normalization or regression.
Conversely, therapeutic strategies focus on stimulating angiogenesis to treat conditions caused by insufficient blood flow. Pro-angiogenic therapies aim to deliver growth factors to encourage new vessel sprouting in ischemic tissues. This approach is investigated for treating heart disease, where new vessels could bypass blocked coronary arteries, and peripheral artery disease, where improved circulation is needed in the limbs. The challenge remains achieving controlled, stable vessel growth in these tissues.