Dear Dr. Zhaung,

You ask an insightful question. Many therapies that have been shown to have significant effect in murine models have failed to show benefit in clinical trials. This has led many to conclude that murine models do not mimic the human condition of PAD. However, many of the murine experiments used conditions that were very different from those that exist in humans with PAD. For example, young healthy mice have been used when humans afflicted with PAD typically have multiple risk factors and comorbidities. Also, some murine models have gone to extremes to produce sustained severe ischemia by excising long segments of limb arteries and veins which of course does not represent the human condition. Vascular compensation to arterial occlusion in humans is impaired with age and other risk factors. We have had some success in mice with vascular risk factors in mimicking impaired compensation(e.g. FASEB J, 25: 1092.17.) The specific model you might use will depend upon a number of factors, including the stage of human disease you want to mimic (e.g subcritical or critical limb ischemia), and the parameters you want to study. We have offered some suggestions for improving the relevancy of murine models for testing novel therapeutics in our review article entitled "Marvels, Mysteries, and Misconceptions of Vascular Compensation to Peripheral Artery Occlusion" PMID: 20141596. One suggestion is to administer treatment beginning several weeks after model creation when any natural compensation has mostly occurred. The specific endpoints you study will depend upon your objective but ideally would include functional reserve or maximal flow capacity as addressed in the review of preclinical PAD models by Waters et al PMID: 15107408.

Best wishes,

Joe