Periprocedural hydrogen sulfide therapy improves vascular remodeling and attenuates vein graft disease

Abstract

BACKGROUND: Failure rates after revascularization surgery remain high, both in vein grafts (VG) and arterial interventions. One promising approach to improve outcomes is endogenous upregulation of the gaseous transmitter-molecule hydrogen sulfide, via short-term dietary restriction. However, strict patient compliance stands as a potential translational barrier in the vascular surgery patient population. Here we present a new therapeutic approach, via a locally applicable gel containing the hydrogen sulfide releasing prodrug (GYY), to both mitigate graft failure and improve arterial remodeling. METHODS AND RESULTS: All experiments were performed on C57BL/6 (male, 12 weeks old) mice. VG surgery was performed by grafting a donor-mouse cava vein into the right common carotid artery of a recipient via an end-to-end anastomosis. In separate experiments arterial intimal hyperplasia was assayed via a right common carotid artery focal stenosis model. All mice were harvested at postoperative day 28 and artery/graft was processed for histology. Efficacy of hydrogen sulfide was first tested via GYY supplementation of drinking water either 1 week before VG surgery (pre-GYY) or starting immediately postoperatively (post-GYY). Pre-GYY mice had a 36.5% decrease in intimal/media+adventitia area ratio compared with controls. GYY in a 40% Pluronic gel (or vehicle) locally applied to the graft/artery had decreased intimal/media area ratios (right common carotid artery) and improved vessel diameters. GYY-geltreated VG had larger diameters at both postoperative days 14 and 28, and a 56.7% reduction in intimal/media+adventitia area ratios. Intimal vascular smooth muscle cell migration was decreased 30.6% after GYY gel treatment, which was reproduced in vitro. CONCLUSIONS: Local gel-based treatment with the hydrogen sulfide-donor GYY stands as a translatable therapy to improve VG durability and arterial remodeling after injury.