Mouse models to study angiogenesis in the context of cardiovascular diseases

Thierry Couffinhal^1,2, Pascale Dufourcq¹, Laurent Barandon^1,2, Lionel Leroux^1,2 , Cecile Duplaa¹

1 Institut National de la Sante et de la Recherche Medicale, Inserm U828, Pessac, France; Universite Victor Segalen Bordeaux 2, Bordeaux, France,² Departement de Cardiologie, Pole cardiothoracique, CHU Groupe Sud, Hopital Haut Leveque, Pessac, France

TABLE OF CONTENTS

1. Abstract

2. Introduction and limits

2.1. Background: angiogenesis, arteriogenesis or vasculogenesis

2.2. Vessel growth in cardiovascular diseases

3. Assessment of angiogenesis, arteriogenesis or vasculogenesis

3.1. Is there an ideal assay to assess neovascularization?

3.2. Monitoring and assessment of angiogenesis, vasculogenesis and arteriogenesis

3.2.1. Imaging vessel morphogenesis

3.2.2. Imaging vessel functions

4. Mouse models to induce neovessel growth

4.1. Model in an Ischemic context

4.1.1. Hindlimb ischemia

4.1.1.1. Original mouse model of hindlimb ischemia

4.1.1.2. Alternative models

4.1.1.3. The mouse model as a preclinical model?

4.1.1.4. Limitations

4.1.2. Heart ischemia

4.1.2.1. Permanent coronary occlusion or ischemia-reperfusion model.

4.1.2.2. Specific myocardial end-points

4.1.3. skin model of graded ischemia

4.2. Model in non ischemic context

4.2.1. Plug assay - disc

4.2.1.1. Matrigel plug assay

4.2.1.2. Model of disc

4.2.2. Eye, retina, cornea

4.2.2.1. Hyaloid vascular system

4.2.2.2. Retinal vascular model

4.2.2.3. Cornea model

4.2.3. Skin Wound healing

4.2.4. Ear model

4.2.5. Ovarian model

5. Cardiovascular risk factor altered animals

5.1. Mouse model of hypercholesterolemia

5.2. Mouse model of diabetes

6. Genetically-engineered animals

6.1. Controlling the spatial and temporal vascular gene expression

6.2. Controlling inhibition of vascular endogenous gene expression

6.3. Conditional expression of the transgene

7. Conclusions

8. Acknowledgment

9. References

1. ABSTRACT

Pathological angiogenesis is a hallmark of various ischemic diseases (insufficient vessel growth) but also of cancer and metastasis, inflammatory diseases, blindness, psoriasis or arthritis (excessive angiogenesis). In response to ischemia (reduced blood flow and oxygen supply), new blood vessels form in order to compensate for the lack of perfusion. This natural process could protect them from the consequences of atherosclerotic diseases (myocardial angina, infarction, hindlimb arteriopathy or stroke). However, neovessel formation is altered in many patients. A better understanding of the mechanisms of functional vessel formation is a pre-requisite to improving the treatment of ischemic pathologies. To this end, it is essential to create easily accessible animal models in which vessel formation can be both manipulated and studied. In this review, we will describe different angiogenic mouse models in the context of cardiovascular diseases, either in an ischemic context (hindlimb ischemia, heart ischemia, skin model) or in a non-ischemic context (plug and eye assay, wound healing, ovarian model). We will also discuss quantitative techniques for assessing angiogenesis in these assays.