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 (H <sub>2</sub> S) works as a vasculoprotective gasotransmitter in vivo. However, given its reactive and hazardous nature, H <sub>2</sub> S is difficult to administer systemically. Here, we developed a hydrogel capable of localized slow release of precise amounts of H <sub>2</sub> S and tested its benefits on IH. The H <sub>2</sub> S-releasing hydrogel was prepared from a short peptide attached to an S-aroylthiooxime H <sub>2</sub> S 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 H <sub>2</sub> S over the course of several hours, in contrast with fast-releasing NaHS. The H <sub>2</sub> S-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 H <sub>2</sub> S-releasing gel limited IH in human great saphenous vein segments obtained from vascular patients undergoing bypass surgery, with the H <sub>2</sub> S-releasing gel showing efficacy at a 5x lower dose than NaHS. These results suggest local perivascular H <sub>2</sub> S 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 (H <sub>2</sub> S) is a gasotransmitter with vasculoprotective properties. Here we designed and synthesized a peptide-based H <sub>2</sub> S-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 H <sub>2</sub> S efficacy against IH in human tissue, and the results show that the gel is more effective than NaHS, a common instantaneous H <sub>2</sub> S donor