Vascular endothelial cells and angiogenesis

Physiological vascular endothelial cell division and angiogenesis occur during embryonic development, wound healing, in the endometrium during the menstrual cycle, and during placental development. Otherwise, vascular endothelial cells divide less than once per decade. Neoplasms are limited in size (∼ 1.0 mm) owing to a deficiency of oxygen and metabolic fuels. To grow larger, new blood vessels form from pre-existing vasculature by angiogenesis (capillary sprouting). During this process, mature endothelial cells replicate and become incorporated into new capillaries resulting in tumor growth. Angiogenesis results in part from the increased production of vascular endothelial growth factors (VEGFs). The human VEGF family consists of VEGF-A/B/C/D and placental growth factor (PlGF). The VEGF family of receptors consists of three protein-tyrosine kinases (VEGFR1/2/3) and two nonprotein kinase receptors (neuropilin-1 and neuropilin-2). Semaphorins 3A-F/4A-G/5 A/B/6A-G/7 A are regulatory ligands that interact with their neuropilin and plexin receptors (PlxA1-A4/B1-B3/C1/D1) and regulate angiogenesis. Angiopoietin-1/2/4 interact with their Tie1/2 receptor protein-tyrosine kinases to modulate vasculogenesis and angiogenesis. Ephrin ligands (EfnA1/A2/A3/A4/A5/B1/B2/B3) and Ephrin receptors (EphA1/A2/A3/A4/A5/A6/A7/A8/A10/B1/B2/B3/B4/B6/) also contribute to angiogenesis. Platelet-derived growth factors, fibroblast growth factors, hepatocyte growth factor (c-Met), stem cell growth factor (Kit) receptor protein-tyrosine kinases, PKB/Akt, Src, and MAP kinases also participate in angiogenesis. Owing to its importance in tumor progression, the inhibition of angiogenic signaling represents an attractive cancer treatment. Ponatinib, regorafenib, and vandetanib are FDA-approved VEGFR, Tie2, and Ephrin receptor blockers used in the treatment of various malignancies. Other disorders characterized by aberrant angiogenesis include diabetic retinopathies and neovascular age-related macular degeneration.