There are several factors that regulate angiogenesis. Some of these factors act as stimulants to angiogenesis or creation of new blood vessels, yet others act as inhibitors to prevent angiogenesis.
To form new capillaries, endothelial cells of existing blood vessels must breakdown the underlying basement membrane of the existing blood vessels.
These processes of endothelial cell activation and penetration require two systems – the Plasminogen Activator system (PA system) and the MMPs.
There are several PAs termed uPAs and tPAs that are serine proteases that convert plasminogen into plasmin. Plasmin acts on ﬁbrin, ﬁbronectin, laminin, and the protein core of the proteoglycans.
Plasmin also activates MMPs such as MMP-1, MMP-3, and MMP-9. These are metalloproteinases.
PAs and MMPs are secreted along with their inhibitors at site of angiogenesis to maintain a strict control of the proteolytic activity, in order to preserve normal tissue structure.
This control is lost during formation of a tumor. MMP levels are high in lung, breast, colorectal, gastric, bladder, cervical, prostate cancers.
Once the proteolysis or basement membrane breakdown takes place the endothelial cells start to migrate through the broken areas. These cells are stimulated by a variety of growth factors.
These are released by the extracellular matrix (ECM). The angiogenesis factors are divided into three classes.
The first class consists of the VEGF family and the angiopoietins. These act especially on the endothelial cells.
VEGF belongs to the VEGF family. There are six members in this family. These include VEGF-A (or VEGF), PlGF, VEGF-B, VEGF-C, VEGF-D, and orf virus VEGF (VEGF-E).
VEGF is vital for survival and development of the fetus. VEGF works by stimulating the breakdown of the ECM along with multiplication, movement and tube formation of endothelial cells. It helps these cells express uPA, PAI-1, uPAR, and MMP-1.
The second class contains direct-acting molecules like cytokines, chemokines and angiogenic enzymes. These target other cells as well.
One of the members of this group is the FGF-2 that was one of the first angiogenic peptides to be characterized. The FGF family has 19 members.
FGF 2 is vital for angiogenesis. It induces multiplication and movement of the cells as well as uPA production by endothelial cells. FGF-2 induces tube formation in collagen gels and alters integrin expression that helps in angiogenesis.
The third group of angiogenic molecules are indirect-acting factors that act by release of direct-acting factors from macrophages, endothelial or tumor cells rather than directly on the endothelial cells. Agents of this group include tumor necrosis factors (TNF a and b).