Abstract 123: Perivascular Adiponectin Attenuates the Neointimal Response Potentially via Modulation of Hydrogen Sulfide

Abstract

Objective: Intimal hyperplasia (IH) limits the durability of vascular interventions. Perivascular adipose serves as scaffolding for vessels and also as a source of adipokines, including adiponectin (APN). The globular domain of adiponectin (gAPN) has high affinity for endothelial AdipoR1 receptors and holds beneficial roles in vascular adaptations. Hydrogen sulfide (H 2 S) is a vasculo-protective gasotransmitter produced by cystathionine γ-lyase (CGL), and low circulating H 2 S levels associate with human vascular disease. We therefore hypothesized that APN knockout (KO) mice would be predisposed to IH, and that local administration of gAPN would protect APN KO mice from IH. Furthermore, we evaluated potential links between APN and H 2 S in these effects. Approach and Results: Wildtype (WT, n=7) and APN KO (n=8) mice maintained on high fat diet were subject to carotid focal stenosis. An additional group of APN KO mice (n=7) were treated by local injection of gAPN suspended in Matrigel. Carotids were harvested 28 days following surgery and analyzed 400-2800μm proximal to the stenosis microscopically. IH area was significantly increased at 400μm in APN KO mice compared to WT (p=<0.05, Fig. A), while gAPN significantly attenuated intimal area compared to untreated KO mice (p=<0.05, Fig. B). This finding was coupled with significant (p=<0.05, Fig. C) decrease in pre-operative baseline serum H 2 S production capacity in APN KO (lead acetate assay) compared to WT. Serum collected upon harvest trended toward increased H 2 S production capacity in APN KO mice treated with gAPN (Fig. D). Kidney CGL expression (Western) revealed a trend for increased in CGL expression in the gAPN group (Fig. E). Conclusion: In a focal stenosis model APN KO mice demonstrated increased distal IH; when administered locally, gAPN significantly attenuated IH. These data also uncover a reduction in H 2 S production capacity in APN KO mice, providing a novel potential link between these potent vasomediators.