Release of endothelial cell-derived growth factor (ECDGF) by heparin

Endothelial cells in vitro produce potent growth-promoting activities collectively known as endothelial cell-derived growth factor (ECDGF). These mitogens (including platelet-derived growth factor [PDGF]-like and non-PDGF-like species) support DNA synthesis and proliferation of smooth muscle cells and fibroblasts in the absence of other defined mitogens. The current study examines interaction of heparin and heparin-related polysaccharides with bovine aortic endothelial (BAE) cells and the levels of secreted growth-promoting activity. Heparin, dextran sulfate, and carageenan rapidly release non-PDGF-like ECDGF from BAE cell monolayers. The effective heparin concentrations closely correlate with amounts of exogenous 3H-heparin required for maximal binding to BAE cells. Both heparin binding and ECDGF release occur independently of incubation temperature. Inhibition of heparin binding by dextran sulfate and carageenan and the lack of inhibition by dextran, chondroitin sulfate, and dermatan sulfate imply a high degree of specificity of the interaction. In contrast to quiescent monolayers of BAE cells, migrating cells release lower levels of growth-promoting activity, and no ECDGF is released in response to heparin, although migrating cells bind the same levels of 3H-heparin as confluent monolayers. Partial characterization of the endothelial cell released mitogens indicates that the non-PDGF-like mitogen is associated with endothelial cell surfaces in contrast to the apparent constitutive release of PDGF-like mitogens. These results indicate that endothelial cells modulate production and release of specific mitogens in response to growth state.