A Reliable Mouse Model of Hind limb Gangrene

Ann Vasc Surg. 2018 Apr:48:222-232. doi: 10.1016/j.avsg.2017.10.008. Epub 2017 Nov 29.

Abstract

Background: Lack of a reliable hind limb gangrene animal model limits preclinical studies of gangrene, a severe form of critical limb ischemia. We develop a novel mouse hind limb gangrene model to facilitate translational studies.

Methods: BALB/c, FVB, and C57BL/6 mice underwent femoral artery ligation (FAL) with or without administration of NG-nitro-L-arginine methyl ester (L-NAME), an endothelial nitric oxide synthase inhibitor. Gangrene was assessed using standardized ischemia scores ranging from 0 (no gangrene) to 12 (forefoot gangrene). Laser Doppler imaging (LDI) and DiI perfusion quantified hind limb reperfusion postoperatively.

Results: BALB/c develops gangrene with FAL-only (n = 11/11, 100% gangrene incidence), showing mean limb ischemia score of 12 on postoperative days (PODs) 7 and 14 with LDI ranging from 0.08 to 0.12 on respective PODs. Most FVB did not develop gangrene with FAL-only (n = 3/9, 33% gangrene incidence) but with FAL and L-NAME (n = 9/9, 100% gangrene incidence). Mean limb ischemia scores for FVB undergoing FAL with L-NAME were significantly higher than for FVB receiving FAL-only. LDI score and capillary density by POD 28 were significantly lower in FVB undergoing FAL with L-NAME. C57BL/6 did not develop gangrene with FAL-only or FAL and L-NAME.

Conclusions: Reproducible murine gangrene models may elucidate molecular mechanisms for gangrene development, facilitating therapeutic intervention.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Blood Flow Velocity
  • Disease Models, Animal
  • Femoral Artery / surgery*
  • Gangrene
  • Hindlimb
  • Ischemia / enzymology
  • Ischemia / etiology*
  • Ischemia / pathology
  • Ischemia / physiopathology
  • Ligation
  • Male
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Muscle, Skeletal / blood supply*
  • Muscle, Skeletal / pathology
  • NG-Nitroarginine Methyl Ester*
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase Type III / antagonists & inhibitors
  • Nitric Oxide Synthase Type III / metabolism
  • Peripheral Arterial Disease / enzymology
  • Peripheral Arterial Disease / etiology*
  • Peripheral Arterial Disease / pathology
  • Peripheral Arterial Disease / physiopathology
  • Regional Blood Flow
  • Species Specificity
  • Time Factors

Substances

  • Nitric Oxide
  • Nitric Oxide Synthase Type III
  • Nos3 protein, mouse
  • NG-Nitroarginine Methyl Ester