ENDOTHELIAL PROTEOGLYCANS INHIBIT BFGF BINDING AND MITOGENESIS

Basic fibroblast growth factor (bFGF) is a known mitogen for vascular smooth muscle cells and has been implicated as having a role in a numb er of proliferative vascular disorders. Binding of bFGF to heparin or heparan sulfate has been demonstrated to both stimulate and inhibit gr owth factor activity. The activity, towards bFGF, of heparan sulfate p roteoglycans present within the vascular system is likely related to t he chemical characteristics of the glycosaminoglycan as well as the st ructure and pericellular location of the intact proteoglycans. We have previously shown that endothelial conditioned medium inhibits both bF GF binding to vascular smooth muscle cells and bFGF stimulated cell pr oliferation in vitro. In the present study, we have isolated proteogly cans from endothelial cell conditioned medium and demonstrated that th ey are responsible for the bFGF inhibitory activity. We further separa ted endothelial secreted proteoglycans into two fractions, PC-A and PG -B. The larger sized fraction (PC-A) had greater inhibitory activity t han did PC-B for both bFGF binding and bFGF stimulation of vascular sm ooth muscle cell proliferation. The increased relative activity of PC- A was attributed, in parr, to larger heparan sulfate chains which were more potent inhibitors of bFGF binding than the smaller heparan sulfa te chains on PG-B. Both proteoglycan fractions contained perlecan-like core proteins; however, PC-A contained an additional core protein (ap proximately 190; kDa) that was not observed in PG-B. Both proteoglycan fractions bound bFGF directly, and PC-A bound a significantly greater relative amount of bFGF than did PG-B. Thus the ability of endothelia l heparan sulfate proteoglycans to bind bFGF and prevent its associati on with vascular smooth muscle cells appears essential for inhibition of bFGF-induced mitogenesis. The production of potent bFGF inhibitory heparan sulfate proteoglycans by endothelial cells might contribute to the maintenance of vascular homeostasis. (C) 1997 Wiley-Liss, Inc.