Angiogenesis and VEGF gradient sensing by endothelial cells

Early writers such as Wilson, Haldane and Crile mention endothelial cells. Wilson (1896) lists them among the cells of salamanders in which Flemming (1891) found a centrosome and attraction-sphere.¹ Haldane (1917) mentions endothelial cells lining the capillaries as part of a delicate regulation connected with breathing.² Crile (1926), quoting Wooldridge as reported by Mathews, argued that the blood together with its endothelial cells may be viewed as living matter. The passage from Mathews gives Wooldridge's view, which Crile adopted, that blood separated from the endothelial cells dies and clots.³

Funk (2015) reviewed cell migration in applied electric fields, a behaviour called electrotaxis. In vitro, many cell types preferred the cathode at field strengths around 0.1 to 10 V/cm. Only a few moved to the anode, and these included human vascular endothelial cells and corneal endothelial cells.⁴ Funk added that bioelectric factors override most chemical gradients. O'Hara-Wright and colleagues (2022) report that electric field-induced angiogenesis has been identified in endothelial cells receiving electrical stimulation, citing Wei and colleagues (2020).⁶

Zakirov and colleagues (2021) modelled how two endothelial cells reach a Notch selection pattern, judged by their Dll4 levels. They note that many aspects of the timing and cell dynamics are not yet understood, largely because live-imaging methods came late.⁷ Their in silico model fixed cells in space. The cells could only extend and retract filopodia into a VEGF gradient, and the authors scored when Notch selection had stably occurred by comparing Dll4 levels between two cells.⁸ They set up the two-cell model to study signatures of active perception.

Angiogenesis also appears in the cancer literature. Rao and colleagues (2015) describe xenografts of prostate cancer cells overexpressing the CaV-α2δ2 subunit. These tumours were more tumorigenic and showed evidence of increased proliferation and angiogenesis.⁵ The authors of the cited study also report that the blocker gabapentin reduced the tumours. Zakirov and colleagues date the discovery of angiogenesis's role in cancer progression to the 1970s.⁷