Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits. Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl hydroxylase and factor inhibiting HIF-1. Hydroxylated HIF1 alpha binds von Hippel Lindau (VHL) E3 ubiquitin ligase and undergoes degradation.

Hypoxia promotes HIF1ɑ accumulation. HIF1ɑ translocate to the nucleus and binds HIF1-beta, forming the HIF1 dimers. HIF dimer associates with CBP/P300 transcriptional regulator and binds HIF1 response elements of target genes, initiating their transcription. Some pro-angiogenic genes regulated by HIF1 include erythropoietin, angiopoietin, and vascular endothelial growth factor (VEGF). VEGF signaling is critical for regulating angiogenesis.

VEGF is a dimeric protein. They bind the transmembrane RTKs called VEGF receptors (VEGFR). They have five isoforms, of which VEGF-A is most important in regulating angiogenesis and binds VEGFR1 with high affinity. VEGFA binding stimulates endothelial cells to differentiate into tip cells. Tip cells express high levels of delta-like notch ligand four or DLL4. DLL4 of tip cells interacts with the notch receptors of the neighboring cells promoting their differentiation to stalk cells.

Another essential ligand/ RTK signaling includes the angiopoietin/ tie-2 receptor that works closely with the VEGF signaling pathway in the latter stages of angiogenesis. Angiogepoeitin 1/ tie-2 signaling promotes endothelial cell survival, initiates vascular branching, and helps stabilize newly formed vessels.

A third ephrin-B/ephrin-B RTK signaling pathway is also essential for angiogenesis and helps specify endothelial cells into arterial and venous cell types.

Apart from these ligand/receptor interactions, some molecules help mediate cell-cell interactions and cell-matrix interactions and regulate angiogenesis. For example, matrix metalloproteases allow basement membrane degradation and endothelial tip migration to the target tissue. Alternatively, protease inhibitors prevent matrix degradation and stabilize them once the vessel is formed. VE-Cadherins, N cadherins, and occludin are essential junctional proteins that stabilize the newly formed endothelial lining.