Elsevier

Vascular Pharmacology

Volume 45, Issue 5, November 2006, Pages 281-301
Vascular Pharmacology

Murine models of myocardial and limb ischemia: Diagnostic end-points and relevance to clinical problems

https://doi.org/10.1016/j.vph.2006.08.008Get rights and content

Abstract

Ischemic disease represents the new epidemic worldwide. Animal models of ischemic disease are useful because they can help us to understand the underlying pathogenetic mechanisms and develop new therapies. The present review article summarizes the results of a consensus conference on the status and future development of experimentation in the field of cardiovascular medicine using murine models of peripheral and myocardial ischemia. The starting point was to recognize the limits of the approach, which mainly derive from species- and disease-related differences in cardiovascular physiology. For instance, the mouse heart beats at a rate 10 times faster than the human heart. Furthermore, healing processes are more rapid in animals, as they rely on mechanisms that may have lost relevance in man. The main objective of the authors was to propose general guidelines, 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

References (109)

  • H. Van Herck et al.

    Assessment of discomfort in laboratory animals

  • Q. Xu

    Mouse models of arteriosclerosis: from arterial injuries to vascular grafts

    Am. J. Pathol.

    (2004)
  • P. Anversa et al.

    Myocardial response to infarction: morphometric measurement of infarct size and myocyte cellular hypertrophy

    Am. J. Pathol.

    (1985)
  • Anversa et al.

    Myocardial infarction in rats: infarct size, myocyte hypertrophy, and capillary growth

    Circ. Res.

    (1986)
  • M. Arras et al.

    Monocyte activation in angiogenesis and collateral growth in the rabbit hindlimb

    J. Clin. Invest.

    (1997)
  • M. Azizi et al.

    Arterial and renal consequences of partial genetic deficiency in tissue kallikrein activity in humans

    J. Clin. Invest.

    (2005)
  • V. Baumans

    Use of animals in experimental research: an ethical dilemma?

    Gene Ther.

    (2004)
  • S. Bergaya et al.

    Decreased flow-dependent dilation in carotid arteries of tissue kallikrein-knockout mice

    Circ. Res.

    (2001)
  • F. Calara et al.

    Spontaneous plaque rupture and secondary thrombosis in apolipoprotein E-deficient and LDL receptor-deficient mice

    J. Pathol.

    (2001)
  • G. Caligiuri et al.

    Myocardial infarction mediated by endothelin receptor signaling in hypercholesterolemic mice

    Proc. Natl. Acad. Sci. U. S. A.

    (1999)
  • G. Caligiuri et al.

    Interleukin-10 deficiency increases atherosclerosis, thrombosis, and low-density lipoproteins in apolipoprotein E knockout mice

    Mol. Med.

    (2003)
  • P. Carmeliet

    Mechanisms of angiogenesis and arteriogenesis

    Nat. Med.

    (2000)
  • D.H. Cherwek et al.

    Fiber type-specific differential expression of angiogenic factors in response to chronic hindlimb ischemia

    Am. J. Physiol, Heart Circ. Physiol.

    (2003)
  • L. Cheval et al.

    SADE: a microassay for serial analysis of gene expression

  • M. Cohen et al.

    Limitation of myocardial ischemia by collateral circulation during sudden controlled coronary artery occlusion in human subjects: a prospective study

    Circulation

    (1986)
  • T. Couffinhal et al.

    A mouse model of angiogenesis

    Am. J. Pathol.

    (1998)
  • T. Couffinhal et al.

    Impaired collateral vessel development associated with reduced expression of Vascular Endothelial Growth Factor in ApoE−/− mice

    Circulation

    (1999)
  • J.N. Crawley

    What's Wrong with My Mouse? Behavioral Phenotyping of Transgenic and Knockout Mice

    (1998)
  • E. Deindl et al.

    Role of ischemia and of hypoxia-inducible genes in arteriogenesis after femoral artery occlusion in the rabbit

    Circ. Res.

    (2001)
  • C.L. Duvall et al.

    Quantitative microcomputed tomography analysis of collateral vessel development after ischemic injury

    Am. J. Physiol, Heart Circ. Physiol.

    (2004)
  • C. Emanueli et al.

    Dilated and failing cardiomyopathy in bradykinin B(2) receptor knockout mice

    Circulation

    (1999)
  • C. Emanueli et al.

    Local delivery of human tissue kallikrein gene accelerates spontaneous angiogenesis in mouse model of hindlimb ischemia

    Circulation

    (2001)
  • C. Emanueli et al.

    Nerve growth factor promotes angiogenesis and arteriogenesis in ischemic hindlimbs

    Circulation

    (2002)
  • C. Emanueli et al.

    Prevention of diabetes-induced microangiopathy by human tissue kallikrein gene transfer

    Circulation

    (2002)
  • C. Emanueli et al.

    Impaired angiogenesis response to limb ischemia in genetically type 2 diabetic mice is corrected by gene therapy with tissue kallikrein or activated Akt-B kinase

    Diabetologia

    (2003)
  • C. Emanueli et al.

    Prophylactic gene therapy with human tissue kallikrein ameliorates limb ischemia recovery in type 1 diabetic mice

    Diabetes

    (2004)
  • C. Emanueli et al.

    Akt/protein kinase B and endothelial nitric oxide synthase mediate muscular neovascularization induced by tissue kallikrein gene transfer

    Circulation

    (2004)
  • M.L. Entman et al.

    Inflammation in the course of early myocardial ischemia

    FASEB J.

    (1991)
  • M.L. Entman et al.

    For want of a few good shams

    Am. J. Physiol.

    (2000)
  • European Convention for the Protection of Vertebrate Animals Used for Experimental and other Scientific Purposes (ETS 123), 1985

    (1985)
  • European Council Directive

    Directive on the Approximation of Laws, Regulations and Administrative Provisions of the Member States Regarding the Protection of Vertebrate Animals Used for Experimental and other Scientific Purposes (86/609/EEC)

    (1986)
  • J. Ezan et al.

    FrzA/sFRP-1, a secreted antagonist of the Wnt-Frizzled pathway, controls vascular cell proliferation in vitro and in vivo

    Cardiovasc. Res.

    (2004)
  • P.M. Farrehi et al.

    Regulation of arterial thrombolysis by plasminogen activator inhibitor-1 in mice

    Circulation

    (1998)
  • N.G. Frangogiannis et al.

    The inflammatory response in myocardial infarction

    Cardiovasc. Res.

    (2002)
  • G. Graiani et al.

    Nerve growth factor promotes reparative angiogenesis and inhibits endothelial apoptosis in cutaneous wounds of Type 1 diabetic mice

    Diabetologia

    (2004)
  • G. Graiani et al.

    Genetic deletion of the p66Shc adaptor protein protects from angiotensin II-induced myocardial damage

    Hypertension

    (2005)
  • P.R. Hansen

    Role of neutrophils in myocardial ischemia and reperfusion

    Circulation

    (1995)
  • M. Heil et al.

    Influence of mechanical, cellular, and molecular factors on collateral artery growth (arteriogenesis)

    Circ. Res.

    (2004)
  • M. Heil et al.

    Collateral artery growth (arteriogenesis) after experimental arterial occlusion is impaired in mice lacking CC-chemokine receptor-2

    Circ. Res.

    (2004)
  • A.L. Hemdahl et al.

    Thrombin inhibitor reduces myocardial infarction in apoE−/− × LDLR−/− mice

    Am. J. Physiol, Heart Circ. Physiol.

    (2004)
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