There are two processes that lead to new blood vessel formation, vasculogenesis and angiogenesis. Blood vessel formation in early development is termed vasculogenesis, initiated by mesodermal stem cells which differentiate in situ to angioblasts and then to endothelial cells. Vasculogenesis occurs during embryogenesis via mesodermal progenitor cells differentiating into endothelial cells. Angiogenesis is a highly coordinated process that requires many associated cells and signals to complete. Insufficient vascularization leads to ischemic conditions which inhibit tissue growth or survival whereas abnormal angiogenesis can promote tumor progression or other diseases such as macular degeneration.
Following vasculogenesis, angiogenesis is a process which includes sprouting and intussusceptive growth of pre-existing blood vessels and subsequent remodeling and maturation to form new vasculature. Developing vasculature requires signals to induce vessel stabilization to prevent nascent vessels from becoming leaky or nonfunctional and subsequent regression back to their original state. Unlike vasculogenesis which happens primarily during the embryonic stage, angiogenesis occurs frequently during adulthood. As long as there are active vessels, new vasculature can be generated following biophysical and physiological cues in the environment, of which the most highly studied are angiogenic factors. Notable angiogenic factors include vascular endothelial growth factor (VEGF), angiopoietin, transforming growth factor, fibroblast growth factor (FGF), hepatocyte growth factor, and platelet-derived growth factor, although dozens of other proteins are also known to participate in blood vessel formation. The importance of several angiogenic factors has been revealed by gene knockout resulting in embryonic lethality.
Angiogenesis can be roughly divided into two phases: the activation phase and the maturation phase. In the activation phase, endothelial cells (ECs) migrate into the extracellular space by penetrating the peri-vascular basement membrane. They continue to proliferate and form capillary sprouts and tubular structures. In the maturation phase, ECs stop migration and proliferation to reconstitute a basement membrane and vessel wall by the recruitment of smooth muscle cells. During this highly regulated process, a balance between pro- and anti-angiogenic factors regulates the sequential steps of angiogenesis. Several growth factors are considered to be pro-angiogenic in this process, including basic FGF, platelet-derived growth factor (PDGF), VEGF, and TGF-β1.
Angiogenesis, the induction and recruitment of new blood vessels from existing vasculature to new tissues has been studied for decades with regards to its role in tumor progression. Blood vessels are composed primarily of endothelial cells that together build a network for the transport of blood allowing for appropriate tissue perfusion. Angiogenesis refers to the development of new capillaries from pre-existing ones. As living cells must normally be within 100 um of nutrient supply it has been shown that in order for any tumor to grow beyond 1-2mm3 requires angiogenesis to occur. Tumors are able to recruit blood vessel development through a disruption in endogenous growth factor secretion. In normal tissues, these growth factors would act synchronously to maintain a balance.
In the ovary there is a normal cyclical trend for the secretion of these factors, which allows for the monthly fluctuations in nutrient demand to the follicles of the ovary. During this cycle, blood vessels are recruited to supply nutrients and to act as a means of hormone delivery as the follicle acquires more tissue layers. Upon maturity the vasculature will then either be re-modeled or will regress from its current location. In contrast, tumor development in the ovary often results from a disruption that does not facilitate the cyclical development of the vasculature; instead there is a transition to a state of perpetual ex
The angiogenic switch occurs in the event of angiogenic factors being expressed in an unbalanced fashion favoring pro-angiogenics and facilitation of angiogenesis. The resultant increase in the delivery of nutrients to the tumor allows the primary lesion to grow and eventually metastasize. There are many molecules that have been shown to participate in this angiogenic switch. Of these factors there are a select group of proteins that are often associated with either the pro- or anti-angiogenic side of the switch, these include: the FGFs and VEGF for the pro-angiogenic side as well as TSP-1, Prolactin, Interferon a/p, platlet factor-4 and Angiostatin for the anti-angiogenic side.
1. Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis[J]. cell, 1996, 86(3): 353-364.
2. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease[J]. Nature medicine, 1995, 1(1): 27-30.
3. Risau W. Mechanisms of angiogenesis[J]. Nature, 1997, 386(6626): 671-674.