Objective
The primary preclinical model of peripheral artery disease (PAD),
which involves acute limb ischemia (ALI), can result in appreciable muscle
injury that is attributed to the acuity of the ischemic injury. A less acute
model of murine limb ischemia using ameroid constrictors (AC) has been
developed in an attempt to mimic the chronic nature of human disease.
However, there is currently little understanding of how genetics influence
muscle injury following subacute arterial occlusion in the mouse.
Methods
We investigated the influence of mouse genetics on skeletal muscle
tissue survival, blood flow, and vascular density by subjecting two
different mouse strains, C57BL/6 (BL6) and BALB/c, to ALI or subacute limb
ischemia (SLI) using single (1AC) or double (2AC) ameroid constrictor
placement on the femoral artery.
Results
Similar to ALI, the 2AC model resulted in significant tissue necrosis
and limb perfusion deficits in genetically susceptible BALB/c but not BL6
mice. In the 1AC model, no outward evidence of tissue necrosis was observed,
and there were no differences in limb blood flow between BL6 and BALB/c.
However, BALB/c mice displayed significantly greater muscle injury, as
evidenced by increased inflammation and myofiber atrophy, despite having no
differences in CD31+ and SMA+ vascular density and
area. BALB/c mice also displayed significantly greater centralized
myonuclei, indicating increased muscle regeneration.
Conclusions
The susceptibility of skeletal muscle to ischemia-induced injury is
at least partly independent of muscle blood flow and vascular density,
consistent with a muscle cell autonomous response that is genetically
determined. Further development of preclinical models of PAD that more
accurately reflect the nature of the human disease may allow more accurate
identification of genetic targets for therapeutic intervention.