Heparan sulfate proteoglycans (HSPGs) are key constituents of subendothelial extracellular matrix that play an important role in the assembly and structure of the basement membrane, regulation of basement membrane permeability, growth factor activity and cellular adhesion. Vascular HSPGs decrease during inflammation, atherosclerosis and diabetes. Recent studies showed that HSPGs are negatively regulated by atherogenic molecules and positively regulated by antiatherogenic agents. Extracellular matrix HSPG, perlecan, appears to be a key target of regulation by these agents. At least two levels of regulation appear to control perlecan HSPG in matrix; a change in core protein expression or a change in heparan sulfate metabolism. Atherogenic levels of low-density lipoprotein (LDL), oxidized LDL and lysolecithin decrease not only perlecan core protein synthesis but also enhance heparan sulfate degradation by stimulating endothelial secretion of heparanase. ApoE and apoE-HDL, in contrast, increase perlecan core protein as well as sulfation of heparan sulfate. Increased perlecan in endothelial cells was associated with increased antithrombin-binding and antiproliferative heparan sulfates. Moreover, modulation of perlecan appears to have a direct effect on smooth muscle cell growth. Thus, lipoprotein modulation of vascular perlecan may play a key role in the modulation of atherogenesis.