Hyaluronan and versican are extracellular matrix (ECM) macromolecules that are present in low amounts in normal blood vessels, but increase dramatically in vascular disease. These ECM components are particularly enriched in intimal hyperplasia as seen in human restenotic lesions following balloon angioplasty and provide a permissive environment for arterial smooth muscle cell (ASMC) proliferation, migration, and macrophage adhesion. Interference with the association of hyaluronan and versican with the surface of ASMCs, either through short oliogosaccharides of hyaluronan or blocking antibodies to the hyaluronan receptor, CD44, blocks the proliferative and migratory response of these cells to growth factors, such as platelet derived growth factor (PDGF). Agents that interfere with the proliferative response of ASMCs and that are used in the treatment of restenosis, such as rapamycin, inhibit the synthesis of hyaluronan by these cells. Inhibition of versican by versican antisense blocks proliferation of SMCs. The synthesis of hyaluronan and versican is highly regulated and influenced by pro-inflammatory growth factors such as PDGF and transforming growth factor-beta (TGF-beta).