Experimental in vivo and ex vivo models for the study of human aortic dissection: promises and challenges

Abstract

Aortic dissection (AD) is a life-threatening aortopathy with high mortality. To mimic spontaneous AD, investigate the pathogenesis of AD and develop novel therapeutic targets and measures, multiple AD experimental models have been generated, including drugs or chemicals induced experimental models, genetically modified experimental models, surgically or invasively induced experimental models, and ex vivo models. However, the perfect model of AD that replicates every aspect of the natural disease has not be generated yet. This review provides an overview of the experimental models used in AD preclinical research. The value and challenges of each in vivo and ex vivo model are discussed.

Keywords: Aortic dissection; angiotensin II; experimental model; marfan syndrome; β-aminopropionitrile monofumarate.

Figure 1

Classification of aortic dissection. Schematic diagram of aortic dissection subdivided into DeBakey Type I, II, and III, or Stanford Type A and B.

Figure 2

Drugs or chemicals induced aortic dissection animal models. A. Wild-type rats were stimulated with 0.25% β-Aminopropionitrile (BAPN) by orally at 3 week-old age for 4 weeks with 64.7-75% incidence of aortic dissection/rupture. B. Wild-type mice were treated with 0.25% BAPN by orally at 3 week-old age for 4 weeks, and then challenged with 1 μg/kg/min of Ang II by Alzet osmotic minipumps for indicated times, and 20%, 80%, 100% aortic dissection incidence was observed after Ang II treated for 6, 12, 24 hours, respectively. C. The wild-type mice were first locally disposed with 0.5 M CaCl₂ at external surface of the infrarenal aorta, and then stimulated with 2 mg/kg/min of Ang II for 2 weeks via Alzet osmotic minipumps. After that the mice were injected with 100 μg/kg/day recombinant murine granulocyte macrophage colony-stimulating factor (GM-CSF) by intraperitoneally for 2 or 4 weeks. D. The adult ApoE^-/- mice were treated by subcutaneous implanting an Alzet osmotic minipumps loaded with 1 mg/kg/min of angiotensin II (Ang II) for 28 days. E. The adult wild-type mice were topically challenged with 30 μL (5 U/mg of protein) of highly concentrated type I porcine pancreatic elastase at infrarenal aorta to induce aortic aneurysm/dissection.

Figure 3

The schematic diagram of ex vivo aortic dissection model. The basic components of device for ex vivo model, including high pressure pump, pressure regulator, electromagnetic sluice gate, aorta with surgically induced dissection, and flow sensor and reservoir.