Storing Growth Factors for Later

Science's STKE  20 Jan 2004:
Vol. 2004, Issue 216, pp. tw24-TW24
DOI: 10.1126/stke.2162004TW24

Vascular endothelial growth factor (VEGF) stimulates the growth of new blood vessels. The interaction of VEGF with the extracellular matrix (ECM) and endothelial cells is enhanced at low pH, which can arise under conditions of hypoxia. Goerges and Nugent analyzed the pH-dependent interactions of VEGF165 (an isoform that binds heparin through a heparin-binding domain) and VEGF121 (an isoform that lacks the heparin-binding domain and does not interact with heparin at neutral pH) with the matrix protein fibronectin. Heparinase treatment of endothelial cells at low pH did not remove all bound VEGF165 and VEGF121, which suggested that, at low pH, binding to another VEGF partner was enhanced. Binding of VEGF165 and VEGF121 to fibronectin was increased at low pH (pH 6.5 or 5.5); however, binding to collagen or bovine serum albumin was unaffected by decreased pH. Binding to fibronectin was reversible when these endothelial cells returned to neutral pH, and the released VEGF was active in stimulating extracellular signal-regulated kinase activity (ERK1 and -2). If VEGF165 was bound to endothelial cells at pH 5.5, there was no ERK phosphorylation until the cells were returned to neutral pH. Addition of low concentrations of heparin to the binding assays increased the interaction of both VEGF121 and VEGF165 with fibronectin-coated dishes at low pH. At neutral pH, the interaction of VEGF121 was not stimulated, which suggested that decreased pH converts this non-heparin-binding isoform to a heparin-binding form. The authors propose that hypoxia reduces extracellular pH, which allows sequestering of VEGF in the ECM and at the surface of the endothelial cells, whereupon return to neutral pH allows these stored growth factors to activate signaling needed to stimulate angiogenesis.

A. L. Goerges, M. A. Nugent, pH regulates vascular endothelial growth factor binding to fibronectin: A mechanism for control of extracellular matrix storage and release. J. Biol. Chem. 279, 2307-2315 (2003). [Abstract] [Full Text]