Homocysteine and cholesterol in the biomechanics and structural remodeling of the aorta during the development of atherosclerosis

In the current work, we investigate the mechanical and structural changes of the thoracic and abdominal aortas in response to high homocysteine and cholesterol conditions. Hyperhomocysteinemia, an elevated homocysteine level in the blood, has been recognized as an independent risk factor for atherosclerosis. Its relationship with aortic biomechanics and its influence on the macromolecular constituents of the aorta have been little studied. We therefore use a rabbit model of atherosclerosis, in which we combined balloon injury of the abdominal aorta, special diets, and intravenous homocysteine injections. Equibiaxial tensile tests, including (i) cyclic step-wise stress relaxation and (ii) continuous cyclic protocols, were carried out to characterize the inelastic behavior of the injured abdominal aorta and the intact thoracic aorta. Mechanical investigation was supplemented by multi-photon microscopy and histology. Our study reveals structural remodeling and changes in the mechanical properties in response to treatments. While a cholesterol-rich diet induced softening of both aortic segments, elevated homocysteine conditions led to intimal collagen deposition and stiffening of the abdominal aorta, even in the absence of hypercholesterolemia, suggesting an independent role of homocysteine in the initiation of atherosclerosis. Interestingly, in rabbits subjected to the combination of high homocysteine and cholesterol conditions, we observed no differences in the stress response compared to the control group, despite medial calcification. Finally, when comparing the two aortic regions, more pronounced inelastic phenomena were measured in the injured abdominal aorta, where atherosclerosis progressed most due to balloon injury, suggesting changes in tissue viscoelasticity as a potential indicator of wall remodeling. Statement of significance: The mechanical properties of the aorta are closely linked to its microstructure. In vascular diseases such as atherosclerosis, the aorta stiffens and remodeling of the aortic wall occurs. The role of the elevated homocysteine levels (hyperhomocysteinemia) in the development of atherosclerosis is not fully understood yet. In this study, we show the effects of treatments with elevated homocysteine and cholesterol conditions, as well as their combination, on the microstructure and passive mechanical properties of the abdominal and thoracic aortas in a rabbit model of atherosclerosis. Under high homocysteine conditions, we observed remodeling and disorganization of the aortic structure, aortic stiffening, and changes in rate-dependent mechanical properties. The results presented here may contribute to improved prevention and treatment of atherosclerosis.