Abstract

Intimal hyperplasia (IH) is the major cause of stenosis of vein grafts. Drugs such as statins prevent stenosis but their systemic administration has limited effects. We developed a hyaluronic acid hydrogel matrix which ensures a controlled release of atorvastatin (ATV) at the site of injury. The release kinetics demonstrated that 100% of ATV was released over 10 h, independently of the loading concentration of the hydrogel. We investigated the effects of such a delivery on primary vascular smooth muscle cells isolated from human veins (HSMCs). ATV decreased HSMCs proliferation, migration and passage across a matrix barrier in a similar dose- (5 -10 μM) and time-dependent manner (24-72 h), whether the drug was directly added to the culture medium or released from the hydrogel. Expression analysis of genes known to be involved in the development of IH, demonstrated that the transcripts of both the gap junction protein Connexin43 (Cx43) and the plasminogen inhibitor PAI-1 were decreased after a 24-48 h exposure to the hydrogel loaded with ATV, whereas the transcripts of the heme oxygenase HO-1 and of the inhibitor of tissue plasminogen activator tPA were increased. At the protein level, Cx43, PAI-1 and the metalloproteinase-9 expression were decreased, whereas HO-1 was upregulated in the presence of ATV. The data demonstrate that the ATV released from a hydrogel has similar effects on HSMCs than the drug freely dissolved in the environment.