Platelet factor 4 modulates the mitogenic activity of basic fibroblast growth factor.
Basic fibroblast growth factor (bFGF) has been shown to stimulate cell proliferation after vascular injury. The mitogenic activity of bFGF requires interactions with both a high affinity receptor and a cell-surface heparan sulfate proteoglycan. We tested the ability of platelet factor 4 (PF 4) and other platelet heparin-binding proteins to modulate bFGF-stimulated [3H]thymidine incorporation into fibroblasts. The supernatant of thrombin-stimulated platelets contained an inhibitor of bFGF-induced mitogenesis; this activity coeluted with PF 4 upon gel filtration, heparin-agarose, and ion-exchange chromatography. Purified thrombospondin and beta-thromboglobulin did not inhibit the mitogenic activity of bFGF. PF 4 inhibited the activity of 5 pM bFGF with 50% inhibitory concentration of 75 nM. Purified PF 4 also inhibited the basal incorporation of [3H]thymidine into 3T3 fibroblasts and the increased [3H]thymidine incorporation occurring after wounding of a cell monolayer. PF 4 did not affect the mitogenic activity of serum. Inhibition of bFGF activity by PF 4 could be overcome by exogenous heparin or chondroitin-4-sulfate, suggesting that inhibition of mitogenesis is caused by binding of PF 4 to cell-surface glycosaminoglycans. These results indicate that an important role of PF 4 released at sites of vascular injury and platelet activation is to control cellular proliferation caused by the release of bFGF from ruptured cells.
Department of Medicine, University of Wisconsin-Madison 53706.
J B
JB
Watson
S B
SB
Getzler
D F
DF
Mosher
D016475:3T3 Cells; D000818:Animals; D002455:Cell Division / Q000187:drug effects*; D002809:Chondroitin Sulfates / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors*; D019812:Heparan Sulfate Proteoglycans; D006493:Heparin / Q000494:pharmacology; D006497:Heparan Sulfate / Q000378:metabolism; D006801:Humans; D051379:Mice; D010978:Platelet Factor 4 / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D011509:Proteoglycans / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism
D002809:Chondroitin Sulfates; D016222:Fibroblast Growth Factor 2; D019812:Heparan Sulfate Proteoglycans; D006493:Heparin; D006497:Heparan Sulfate; D010978:Platelet Factor 4; D011509:Proteoglycans; D013936:Thymidine