title: Resolvin D2 Enhances Postischemic Revascularization While Resolving Inflammation.
abstract: Resolvins are lipid mediators generated by leukocytes during the resolution phase of inflammation. They have been shown to regulate the transition from inflammation to tissue repair; however, it is unknown whether resolvins play a role in tissue revascularization following ischemia.
  
  
  
  We used a murine model of hind limb ischemia (HLI), coupled with laser Doppler perfusion imaging, microcomputed tomography, and targeted mass spectrometry, to assess the role of resolvins in revascularization and inflammation resolution.
  
  
  
  In mice undergoing HLI, we identified resolvin D2 (RvD2) in bone marrow and skeletal muscle by mass spectrometry (n=4-7 per group). We also identified RvD2 in skeletal muscle biopsies from humans with peripheral artery disease. Monocytes were recruited to skeletal muscle during HLI and isolated monocytes produced RvD2 in a lipoxygenase-dependent manner. Exogenous RvD2 enhanced perfusion recovery in HLI and microcomputed tomography of limb vasculature revealed greater volume, with evidence of tortuous arterioles indicative of arteriogenesis (n=6-8 per group). Unlike other treatment strategies for therapeutic revascularization that exacerbate inflammation, RvD2 did not increase vascular permeability, but reduced neutrophil accumulation and the plasma levels of tumor necrosis factor-α and granulocyte macrophage colony-stimulating factor. In mice treated with RvD2, histopathologic analysis of skeletal muscle of ischemic limbs showed more regenerating myocytes with centrally located nuclei. RvD2 enhanced endothelial cell migration in a Rac-dependent manner, via its receptor, GPR18, and Gpr18-deficient mice had an endogenous defect in perfusion recovery following HLI. Importantly, RvD2 rescued defective revascularization in diabetic mice.
  
  
  
  RvD2 stimulates arteriogenic revascularization during HLI, suggesting that resolvins may be a novel class of mediators that both resolve inflammation and promote arteriogenesis.
authors: Institute of Molecular Cardiology, Diabetes and Obesity Center, Division of Cardiovascular Medicine, University of Louisville School of Medicine, Louisville, KY.
authors: Michael J
authors: MJ
authors: Zhang
authors: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Harvard Institutes of Medicine, Boston, MA.
authors: Brian E
authors: BE
authors: Sansbury
authors: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Harvard Institutes of Medicine, Boston, MA.
authors: Jason
authors: J
authors: Hellmann
authors: Institute of Molecular Cardiology, Diabetes and Obesity Center, Division of Cardiovascular Medicine, University of Louisville School of Medicine, Louisville, KY.
authors: James F
authors: JF
authors: Baker
authors: Institute of Molecular Cardiology, Diabetes and Obesity Center, Division of Cardiovascular Medicine, University of Louisville School of Medicine, Louisville, KY.
authors: Luping
authors: L
authors: Guo
authors: Vascular Medicine Section, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
authors: Caitlin M
authors: CM
authors: Parmer
authors: Vascular Medicine Section, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
authors: Joshua C
authors: JC
authors: Prenner
authors: Institute of Molecular Cardiology, Diabetes and Obesity Center, Division of Cardiovascular Medicine, University of Louisville School of Medicine, Louisville, KY.
authors: Daniel J
authors: DJ
authors: Conklin
authors: Institute of Molecular Cardiology, Diabetes and Obesity Center, Division of Cardiovascular Medicine, University of Louisville School of Medicine, Louisville, KY.
authors: Aruni
authors: A
authors: Bhatnagar
authors: Vascular Medicine Section, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
authors: Mark A
authors: MA
authors: Creager
authors: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Harvard Institutes of Medicine, Boston, MA.
authors: Matthew
authors: M
authors: Spite
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D015331:Cohort Studies; D004281:Docosahexaenoic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006614:Hindlimb / Q000098:blood supply*; D006801:Humans; D007249:Inflammation / Q000175:diagnosis / Q000188:drug therapy / Q000503:physiopathology; D007511:Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D008875:Middle Aged; D058729:Peripheral Arterial Disease / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: C545423:resolvin D2; D004281:Docosahexaenoic Acids
keywords: imaging techniques; inflammation; peripheral vascular diseases; revascularization