Release of endothelial cell‐derived growth factor (ECDGAF) by heparin

Abstract

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.

Basic fibroblast growth factor and transforming growth factor beta‐1: Synergistic mediators of angiogenesis in vitro

“…Heparin-like molecules present in extracellular matrices could provide a reservoir for bFGF sequestration and subsequent delivery to the high affinity receptors on the cell surface (Moscatelli, 1987(Moscatelli, , 1988Vlodavsky et al, 1987), as demonstrated in bFGF-preincubated endothelial cell cultures (Rifkin et al, 1991) where heparin addition released extracellular matrixbound bFGF. However, since heparin had by itself little effect on morphology or on two-or three-dimensional cell migration, this suggested that substantial levels of extracellular or matrix-associated bFGF were not present in our cultures (Gajdusek and Schwartz, 1984;Gajdusek and Carbon, 1989). TGF-b is a multifunctional mediator (Roberts and Sporn, 1989) with diverse effects on endothelial cell proliferation (Baird and Durkin, 1986;Frater-Schroder et al, 1986), migration (Heimark et al, 1986;Muller et al, 1987;Sat0 and Rifkin, 1989), and expression of extracellular matrix proteins (Roberts and Sporn, 1989).…”

Replication of smooth muscle cells in vascular disease.

“…Part of this activity is due to a material which competes with the PDGF receptor and is neutralized by the PDGF antibody. The identity of the non-PDGF mitogen remains unknown (DiCorleto, 1984;Gajdusek, 1984). The PDGF gene is expressed at high levels by cultured endothelial cells, whereas only low levels of expression of the PDGF gene are seen in endothelium in vivo (Barrett et al, 1983).…”

Cell biology of arterial proteoglycans.

“…174 Heparin also releases ECGF from the surface of cultured endothelial cells. 177 Although the mechanism of heparin action is unclear, the synergistic activity suggests struc-tural interactions between the carbohydrate and mitogen. It is possible that heparin potentiates the activity of ECGF by causing the mitogen to assume a conformation with increased affinity for its receptor.…”