Abstract 17194: Inflammation-resolving Lipid Mediator Resolvin D2 Enhances Revascularization in Hind Limb Ischemia
Critical limb ischemia (CLI) due to occlusive vascular disease increases the risk for limb loss; however, treatment remains an important challenge despite state-of-the-art clinical care. Extensive evidence demonstrates that monocytes/macrophages enhance revascularization during CLI by promoting blood vessel growth, extracellular matrix remodeling and dead tissue removal. Resolvins are a family of lipid mediators generated by macrophages during the resolution phase of inflammation that potently resolve inflammation and promote tissue repair. Therefore, we tested the hypothesis that resolvin D2 (RvD2) enhances revascularization during hind limb ischemia (HLI). Isolated mouse splenic monocytes produced RvD2 and delivery of RvD2 (4μg/kg/day; s.c.) enhanced perfusion recovery after femoral artery/vein ligation and bisection, as assessed by laser Doppler perfusion imaging. By day 14, the mean perfusion in RvD2-treated limbs was significantly higher than with vehicle (64% vs. 29% compared to non-ischemic limb; p<0.05). Stereoscopic microCT scans of Microfil-casted limbs revealed greater vascular volume in RvD2-treated limbs (see figure). The rapid restoration of perfusion and visual evidence of tortuous arterioles suggests the primary mechanism of RvD2-enhanced recovery is through the stimulation of arteriogenesis. Histopathological analysis of RvD2-treated limbs showed reduced disruption of muscle fiber striation and more regenerating myocytes with centrally located nuclei. Consistent with its inflammation-resolving actions, RvD2 decreased plasma levels of TNF-α and increased IL-10 and IL-4. In microvascular endothelial cells, RvD2 enhanced migration in a Rac1 and eNOS-dependent manner. These results suggest that monocyte-derived RvD2 stimulates arteriogenic revascularization after HLI. Thus, resolvins represent a novel class of therapeutics that could potentially both resolve inflammation and promote arteriogenesis.
Author Disclosures: M.J. Zhang: None. J. Hellmann: None. J.F. Baker: None. L. Guo: None. D.J. Conklin: None. A. Bhatnagar: None. M. Spite: None.
- © 2014 by American Heart Association, Inc.