Murine models of myocardial and limb ischemia: Diagnostic end-points and relevance to clinical problems
Section snippets
Models of myocardial ischemia
Atherosclerosis is characterized by accumulation of lipids and fibrous elements in the arteries. Lipid build-up starts with “fatty streaks” in early adolescence and develops into “fibrous lesions” in midlife but may advance faster depending on environmental factors such as high-fat diet and lack of exercise, smoking or infectious agents. As the atherosclerotic lesion becomes larger, the arterial lumen narrows until it hampers the blood flow and leads to clinical manifestations such as unstable
Models of peripheral ischemia
Experimental hindlimb ischemia models have been developed in both small and large animals. In general, large-animal models benefit from the ease of accurate identification of the lower extremity inflow vessels and their branches, as well as a multitude of blood flow measures that can be used throughout the course of a study. Small-animal models benefit from the availability of transgenic lines and genetic tools for analyzing alterations in gene and protein expression.
Demographic factors and diabetes
A number of demographic and clinical factors could impair reparative angiogenesis. Evidence indicates more extensive and sustainable ischemia in diabetic, hypercholesterolemic, hyperhomocysteinemic, or aged mice. For example, femoral artery ligation and excision in non-obese mice, which develop a form of diabetes having clinical features similar to humans with Type I diabetes mellitus, results in an LDPI ratio of 0.5 at 35 days, whereas control animals showed almost completely recovered
Mouse model of vein bypass graft atherosclerosis
Autologous vein grafts are commonly used to replace arteries rendered useless by severe atherosclerosis. Although the treatment is highly successful in relieving symptoms and prolonging survival, graft failure often occurs due to the accelerated atherosclerosis within the grafted vessel conduits (Motwani and Topol, 1998). The pathogenesis of this disease is poorly understood, and no effective clinical intervention is available. A mouse vein graft model was recently established. Using this
Models and therapy
Animal models can be used to assess the potential utility of therapeutics aimed at augmenting perfusion to the ischemic tissue, so the timing of the perfusion assessments is critical. Because all models of hindlimb ischemia are associated with some degree of perfusion recovery, interventions or agents tested at the time of surgery, or shortly after, will measure the capacity of an agent to improve on the degree of recovery. At later time points after surgery (typically more than 1 week), the
Ethical and legislative aspects of animal models of ischemia
The use of animals in experimental research parallels the evolution of medicine. The development of biomedical disciplines as microbiology, pharmacology, toxicology and immunology caused a sharp increase in the use of animals in the 20th century. From the early 1980s, a decrease started probably due to public awareness and strict legislation on animal use, the development of animal ethics committees and an improved quality of laboratory animals. However, in the last decades the use of animals
Conclusions
Regenerative medicine based on the use of angiogenic factors and vascular progenitor cell holds new promises for the cure of ischemic disease. The promotion of a substantial level of tissue neovascularization following ischemic injury is now recognized as one of the most potent strategies to promote tissue repair, protect against ventricular remodelling, and enhance postischemic cardiac performance. Murine models of human disease with dysregulated angiogenesis are useful not only because they
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