Vascular Endothelial Growth Factor (VEGF)

Vascular endothelial growth factor is a family of secreted glycoproteins of which VEGF-A is the dominant angiogenic member, expressed as splice isoforms that differ in how tightly they bind heparan sulphate and so in how far they diffuse from the cell that made them. Signalling runs chiefly through VEGFR-2 on endothelial cells, with neuropilins as co-receptors and VEGFR-1 acting largely as a decoy. Hypoxia is the main stimulus, acting through HIF-1alpha, which is why ischaemic tissue recruits vessels. The immediate effects are increased permeability, endothelial proliferation and migration, and selection of tip and stalk cells for a sprout.

The therapeutic record is lopsided. Blocking this pathway works: bevacizumab was approved in oncology in 2004, and ranibizumab and later aflibercept transformed treatment of neovascular age-related macular degeneration, with class effects including hypertension, proteinuria and impaired wound healing serious enough that surgery is spaced around dosing. Supplying it has not worked. Therapeutic angiogenesis trials delivering VEGF as protein or gene therapy in coronary and limb ischaemia repeatedly failed to beat placebo, despite convincing animal data beforehand.

That asymmetry is the lesson. Vessels formed by a single growth factor without PDGF signalling and pericyte recruitment are leaky, immature and prone to regress, so raising VEGF for a while is not building a durable circulation, and permeability effects can cause oedema before any benefit appears.

The error in repair marketing is to treat upregulates VEGF as a healing claim. It is usually an ELISA on cell-culture supernatant or a stain in rodent granulation tissue. Given that human trials of VEGF delivery failed, an indirect induction in a dish is weak grounds for expecting angiogenesis in a person, and stimulating this pathway is not risk-free.