Angiogenesis - Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors (HIF-PHIs)
Angiogenesis is the growth of new blood vessels from the existing vasculature. This process is involved in development, wound healing, embryo formation and tumor growth. Activation of angiogenesis leads to the release of pro-angiogenic growth factors such as VEGF, PDGF, FGF and TGF, which bind their receptors on endothelial cells within pre-existing vessels. As a result, it induces signal transduction of various pathways such as PI3K/Akt, Erk1/2, Smad and Notch, causing endothelial cells proliferation and migration. Endothelial cells use matrix metalloproteases and integrins to digest extracellular matrix and migrate into new area, where they lengthen and form tubes, generating new blood vessel.
During tumor angiogenesis, cancer cells stimulate formation of new blood vessel for delivering oxygen and nutrients to a tumor. As the tumor grows, cells at the center of the mass become starved of oxygen, causing hypoxia. It stabilizes the expression of a transcription factor, HIF-1α (hypoxia inducible factor-1), which binds HIF-1β to upregulate the expression of several angiogenesis-promoting genes. Moreover, growth factor signaling also stimulates HIF-1 activity in order to maintain oxygen homeostasis for growing cells.