Possible mechanism for lead inhibition of vascular endothelial cell proliferation: a lower response to basic fibroblast growth factor through inhibition of heparan sulfate synthesis.
Although lead inhibits the proliferation of vascular endothelial cells, the mechanism has been incompletely understood. A lower response to basic fibroblast growth factor (bFGF) of growing bovine aortic endothelial cells after exposure to lead was investigated using a cell culture system in the present study. It was shown that lead significantly decreased the incorporation of [3H]thymidine into the acid-insoluble fraction of the cells but the inhibition disappeared in the presence of bFGF neutralizing antibody. Pretreatment with lead resulted in a reduction of the stimulation by exogenous bFGF on the [3H]thymidine incorporation. Lead decreased endogenous bFGF bound to cell surface heparan sulfate proteoglycans in a concentration-dependent manner but not the high affinity FGF receptor without a change of the accumulation within the cells. In spite of such a change in the endogenous bFGF distribution, the total amount of the growth factor synthesized was not significantly changed by lead. Although the binding of [125I]bFGF to heparan sulfate proteoglycans can be directly inhibited by lead, the inhibition was not so marked. On the other hand, lead markedly suppressed the incorporation of [35S]sulfate into heparan sulfate accumulated in the cell layer and the conditioned medium, suggesting that the metal inhibited the synthesis of the glycosaminoglycan in growing endothelial cells. Inhibition of the [3H]thymidine incorporation by lead was significantly restored by heparin. Since the binding of bFGF to its receptor is strongly promoted by heparan sulfate, the present data suggest that lead inhibits vascular endothelial cell proliferation by induction of a lower response to endogenous bFGF through a suppression of heparan sulfate synthesis.
Fujiwara
Y
Y
Department of Environmental Health, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan.
Kaji
T
T
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D006131:Growth Inhibitors / Q000633:toxicity*; D006497:Heparan Sulfate / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D007457:Iodine Radioisotopes; D007854:Lead / Q000633:toxicity*; D013462:Sulfur Radioisotopes
D016222:Fibroblast Growth Factor 2; D006131:Growth Inhibitors; D006497:Heparan Sulfate; D007074:Immunoglobulin G; D007457:Iodine Radioisotopes; D007854:Lead; D013462:Sulfur Radioisotopes