Angiogenesis

Angiogenesis is the growth of new capillaries by sprouting from vessels that already exist, distinct from the embryonic assembly of vessels from progenitor cells. The usual trigger is hypoxia: low tissue oxygen stabilises hypoxia-inducible factor, which drives transcription of vascular endothelial growth factor. VEGF selects a leading tip cell that migrates, while Notch and DLL4 signalling from it suppresses that phenotype in the neighbours, which become stalk cells and form the lumen behind.

The clinical record cuts both ways. Blocking angiogenesis works: bevacizumab, approved in 2004, and the intravitreal VEGF blockers used in wet macular degeneration are established therapies. Promoting it has gone far worse. Growth-factor and gene-therapy programmes aimed at building collateral circulation in critical limb ischaemia and refractory angina produced repeated neutral phase 3 results despite convincing animal data, and none reached approval.

Angiogenesis is therefore a mechanism, not an outcome. A compound that raises VEGF expression or produces more sprouts in an endothelial tube-formation assay has affected a process, not shown that a wound closes faster or an ischaemic limb is salvaged. Whether the new vessels are perfused, patent and stable rather than leaky and regressing within days is where most candidates have failed.

Two misreadings recur. The first is treating angiogenic activity as unambiguously good; the same pathway feeds tumour growth and proliferative retinopathy, so any systemic pro-angiogenic agent carries an obvious theoretical burden. The second is quoting in-vitro or rodent data for repair peptides as clinical evidence. For the commonly marketed repair peptides the angiogenic claims rest entirely on cell culture and small-animal work, with no angiogenesis endpoint measured in any controlled human trial.