B. Wu1, A. Chatterjee1, G. Mottola1, E. Werlin1, M. Chen1, K. D. Lance2, T. A. Desai2, M. S. Conte1 1University Of California – San Francisco,Vascular Surgery,San Francisco, CA, USA 2University Of California – San Francisco,Bioengineering,San Francisco, CA, USA
Introduction: Persistent inflammation following vascular injury is a driver of neointimal hyperplasia. Recent work demonstrates that specialized lipid mediators derived from omega-3 polyunsaturated fatty acids, such as Resolvin D1 (RvD1), actively orchestrate the process of resolution. We investigated local perivascular delivery of RvD1 in a rabbit vein graft model.
Methods: Ipsilateral jugular veins were implanted as carotid interposition grafts via an anastomotic cuff model in New Zealand white rabbits (3-4 kg; N=68). RvD1 (1000 ng) was delivered to the vein bypass grafts in a perivascular fashion, using either 25% Pluronic F127 gel or a thin bi-layered biodegradable poly-lactic-co-glycolic acid (PLGA) wrap. Drug delivery to rabbit veins was confirmed ex-vivo by LC-MS-MS and ELISA. Leukocyte infiltration and cell proliferation were evaluated at 3 days post-bypass via immunohistochemistry. Morphometric analysis was conducted at 28 days post-bypass to evaluate vein graft remodeling.
Results: Perivascular constructs did not influence rates of graft thrombosis, wound infection or death. Leukocyte (CD45) and macrophage (CD68) infiltration was significantly reduced in the RvD1-gel group versus bypass-only and vehicle-gel groups at 3 days (60-72% reduction, P < .01). Cellular proliferation (Ki-67 index) was significantly lower in RvD1-gel grafts versus both bypass-only and vehicle-gel grafts at 3 days (43% and 45% reduction respectively, P < .01). Treatment of vein grafts with RvD1-loaded gels reduced neointimal thickness at 28 days by 61% versus bypass-only grafts (P < .001) and by 63% versus vehicle-gel grafts (P < .001). RvD1-loaded PLGA wraps reduced neointimal formation at 28 days by 50% versus the bypass-only group (P < .001). There was a trend towards decreased graft neointimal thickness for RvD1-loaded wraps versus vehicle-wraps at 28 days, however this did not reach statistical significance (32% reduction, P = .085) [Figure].
Conclusion: Local perivascular delivery of the pro-resolving lipid mediator RvD1 attenuates formation of neointimal hyperplasia without associated toxicity in a rabbit vein graft model. This effect appears to be mediated by both reduced leukocyte recruitment and attenuated cell proliferation in the graft. Perivascular PLGA wraps may also impart protection via external biomechanical scaffolding in this model. Our studies provide further support for the potential therapeutic role of D-series resolvins in modulating vascular injury and repair.
