Hydrogen sulfide-releasing peptide hydrogel limits the development of intimal hyperplasia in human vein segments.

Currently available interventions for vascular occlusive diseases suffer from high failure rates due to re-occlusive vascular wall adaptations, a process called intimal hyperplasia (IH). Naturally occurring hydrogen sulfide (HS) works as a vasculoprotective gasotransmitter in vivo. However, given its reactive and hazardous nature, HS is difficult to administer systemically. Here, we developed a hydrogel capable of localized slow release of precise amounts of HS and tested its benefits on IH. The HS-releasing hydrogel was prepared from a short peptide attached to an S-aroylthiooxime HS donor. Upon dissolution in aqueous buffer, the peptide self-assembled into nanofibers, which formed a gel in the presence of calcium. This new hydrogel delivered HS over the course of several hours, in contrast with fast-releasing NaHS. The HS-releasing peptide/gel inhibited proliferation and migration of primary human vascular smooth muscle cells (VSMCs), while promoting proliferation and migration of human umbilical endothelial cells (ECs). Both NaHS and the HS-releasing gel limited IH in human great saphenous vein segments obtained from vascular patients undergoing bypass surgery, with the HS-releasing gel showing efficacy at a 5x lower dose than NaHS. These results suggest local perivascular HS release as a new strategy to limit VSMC proliferation and IH while promoting EC proliferation, hence re-endothelialization. STATEMENT OF SIGNIFICANCE: Arterial occlusive disease is the leading cause of death in Western countries, yet current therapies suffer from high failure rates due to intimal hyperplasia (IH), a thickening of the vascular wall leading to secondary vessel occlusion. Hydrogen sulfide (HS) is a gasotransmitter with vasculoprotective properties. Here we designed and synthesized a peptide-based HS-releasing hydrogel and found that local application of the gel reduced IH in human vein segments obtained from patients undergoing bypass surgery. This work provides the first evidence of HS efficacy against IH in human tissue, and the results show that the gel is more effective than NaHS, a common instantaneous HS donor.