Experimental aortic aneurysm severity and growth depend on topical elastase concentration and lysyl oxidase inhibition

Alycia G Berman,Daniel J Romary,Morgan M Wigand,Abigail D Cox,Craig J Goergen,Sourav S Patnaik,Ender A Finol,Natalyn E Gorazd,Katherine E Kerr

doi:10.1038/s41598-021-04089-8

Abstract

Abdominal aortic aneurysm (AAA) formation and expansion is highly complex and multifactorial, and the improvement of animal models is an important step to enhance our understanding of AAA pathophysiology. In this study, we explore our ability to influence aneurysm growth in a topical elastase plus β-Aminopropionitrile (BAPN) mouse model by varying elastase concentration and by altering the cross-linking capability of the tissue. To do so, we assess both chronic and acute effects of elastase concentration using volumetric ultrasound. Our results suggest that the applied elastase concentration affects initial elastin degradation, as well as long-term vessel expansion. Additionally, we assessed the effects of BAPN by (1) removing it to restore the cross-linking capability of tissue after aneurysm formation and (2) adding it to animals with stable aneurysms to interrupt cross-linking. These results demonstrate that, even after aneurysm formation, lysyl oxidase inhibition remains necessary for continued expansion. Removing BAPN reduces the aneurysm growth rate to near zero, resulting in a stable aneurysm. In contrast, adding BAPN causes a stable aneurysm to expand. Altogether, these results demonstrate the ability of elastase concentration and BAPN to modulate aneurysm growth rate and severity. The findings open several new areas of investigation in a murine model that mimics many aspects of human AAA.

Highlights

Abdominal aortic aneurysm (AAA) formation and expansion is highly complex and multifactorial, and the improvement of animal models is an important step to enhance our understanding of AAA pathophysiology
Elastase concentration clearly influenced final aneurysm size, with the 2.5 mg/ml elastase application resulting in moderately sized aneurysms and the 5 and 10 mg/ml elastase application resulting in significantly larger aneurysms
The formation and expansion of an AAA is highly complex and multifactorial, and the ability to improve patient care is heavily dependent on increasing our understanding of aneurysm pathophysiology

Summary

Introduction

Abdominal aortic aneurysm (AAA) formation and expansion is highly complex and multifactorial, and the improvement of animal models is an important step to enhance our understanding of AAA pathophysiology. We assessed the effects of BAPN by (1) removing it to restore the cross-linking capability of tissue after aneurysm formation and (2) adding it to animals with stable aneurysms to interrupt cross-linking. These results demonstrate that, even after aneurysm formation, lysyl oxidase inhibition remains necessary for continued expansion. Adding BAPN causes a stable aneurysm to expand These results demonstrate the ability of elastase concentration and BAPN to modulate aneurysm growth rate and severity. Lu and colleagues noted the presence of ILT in some animals, which is of particular interest given the small number of murine aneurysm models that develop ILT, despite its prevalence in many AAA patients

Methods

Results

Conclusion