Infoscience

Thesis

Biomechanical analysis of cerebral arteries: role of elastin and its implication in aging and cerebrovascular disease

The intent of this thesis is to study the function of elastin in cerebral arteries, its contribution into the aging process and its implication into different cerebral diseases and in particular cerebral aneurysms. As of today, little is known on the genesis, growth and rupture of cerebral aneurysm. It is widely thought that these lesions rupture when hemodynamically induced wall stress exceeds wall strength. Therefore, there is a clear need for biomechanical analysis of the aneurysmal wall, which would include precise characterization of the stress and strain field experienced in vivo. The characterization of the stress and strain field requires knowledge of geometry, loading conditions as well as precise knowledge of the elastic properties of the aneurysmal and adjacent parent vessel walls. Because elastin is relatively absent in the aneurismal wall and elastin destruction is thought to be part of the aneurysm formation process, one of the main goals of this thesis was to characterize the effects of elastin degradation on the mechanical properties of arteries while assessed with a constituent-based strain energy function developed by Zulliger et al (*). The first chapter had as primary objective to assess the contribution of elastin on the biomechanical properties of the rabbit common carotid wall, by selectively destructing elastin with elastase. The second objective was to assess the interaction of elastin with the other structural elements and in particular with collagen and its fiber engagement profile. A number of earlier studies have reported that aging process affects elastin, a key component of the arterial wall integrity and functionality as shown in chapter one. Thus, the part two of this thesis focused on the effects of aging on the biomechanical properties human cerebral arteries and in particular on the contribution of elastin. Cerebral arteries from human cadavers were analyzed biomechanically and morphologically in order to quantify the structural remodeling with aging. The effects of aging on functionality of elastin were assessed via selective enzymatic degradation and structural analysis of the elastin. Furthermore, quantification of desmosine and fibrillin cross-linking were evaluated. The main conclusion is that elastin, although physically present as evidenced by histology, is not functional with minimal contribution to the elasticity of aged cerebral wall. Reduced elasticity and non-functional elastin may affect the metabolism of endothelial and medial cells with important clinical implications in relation to the development of cerebrovascular disease. In the third part of this thesis, we were concerned with methods to collect aneurysmal tissues from different clinical centers for later mechanical testing. Thus, the effect of cryopreservation on the arterial matrix was analyzed in the absence of vascular smooth muscle cells. The experiments provided evidence cryopreservation affects only marginally extracellular matrix (ECM), suggesting thus that changes observed in arterial properties after cryopreservation are likely attributed to VSM cells, either as a direct result of VSM cells damage or as indirect effects of VSM cells injury on ECM. The study results also suggested that acellular tissues (i.e., cerebral aneurysms) can be stored without damage at -80°C with cryoprotectant agents (CPA) for later mechanical testing. In the fourth part, we sought a correlation between non-invasively measured biomechanical properties of common carotid arteries and the existence of cerebral aneurysms. This was based on earlier studies, which have showed that risk for cardiovascular events may be assessed by noninvasively measured markers such as stiffness or high pulse pressure. To that end, we measured geometry and elasticity of human carotids in patients with and without cerebral aneurysms. The findings suggested that patients carrying a cerebral aneurysm, present significantly higher diameters of the common carotid arteries at diastolic pressures and, furthermore, the diameters exhibit significantly higher asymmetry, as expressed by the difference between the left and right common carotid systolic and diastolic diameters. This asymmetry in diameters (and likely in other biomechanical properties) may be exploited as clinical indicators for the existence or future development of cerebral aneurysms. Larger clinical studies are required to reconfirm our interesting, yet preliminary findings. ---------------------------------------- (*) Zulliger MA, Rachev A, Stergiopulos N. A constitutive formulation of arterial mechanics including vascular smooth muscle tone. Am J Physiol Heart Circ Physiol. 2004;287:H1335-1343

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