Cadmium induces the production of high molecular weight heparan sulfate proteoglycan molecules in cultured vascular endothelial cells.

The purpose of the present study is to clarify whether or not cadmium-induced production of heparan sulfate in vascular endothelial cells includes: (1) an increase in the number of heparan sulfate proteoglycan (HSPG) molecules; (2) a formation of longer chains of heparan sulfate; and (3) a binding of more heparan sulfate chains to core proteins. Bovine aortic endothelial cells were cultured and metabolically labeled with [(3)H]glucosamine and [(35)S]sulfate in the presence of cadmium chloride. Radiolabeled HSPGs were separated from more highly charged chondroitin or dermatan sulfate proteoglycans by ion-exchange chromatography and hydrodynamic size of HSPGs was characterized by gel filtration. Heparan sulfate chains were characterized by gel filtration after digestion with either papain or heparitinase. It was found that cadmium increases the incorporation of radioactive precursors into the high molecular weight subclass of HSPGs without a marked change of molecular weight of heparan sulfate chains (approximately 45 kDa). A sodium dodecyl sulfate-polyacrylamide gel electrophoresis of [(35)S]methionine-labeled proteins after heparitinase digestion revealed that the endothelial cells actively produce a HSPG core with a high molecular weight (∼400 kDa), probably a perlecan core and the accumulation was increased by cadmium. HSPGs produced by cadmium-treated endothelial cells enhanced the [(3)H]thymidine incorporation in vascular smooth muscle cells cultured in the presence of basic fibroblast growth factor. It was therefore suggested that vascular endothelial cells after exposure to cadmium produce more perlecan molecules and this alteration may contribute to the antithrombogenic property of vascular wall and the formation of atherosclerosis after exposure to the metal through increase in anticoagulant heparan sulfate chains and stimulation of vascular smooth muscle proliferation, respectively.