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The ageing aorta

Boek - Dissertatie

Ondertitel:pathophysiological investigation of aortic stiffness and its temporal relationship to peripheral hypertension and cardiac disease
Arterial stiffness is defined as the impaired capacity of large arteries to cushion the pulsatile blood flow which is generated by the heart, and is recognized as an important and independent predictor of cardiovascular complications. In this doctoral thesis, we aimed to investigate the mechanisms of aortic stiffness in four well-known small animal models of cardiovascular ageing and disease, and we assessed the temporal relationship of aortic stiffness and associated cardiovascular disease parameters. We demonstrated that aortic stiffening precedes peripheral hypertension in ageing C57Bl/6 mice, chronic L-NAME treated mice, and AngII-treated mice. In eNOS knockout mice, age-dependent arterial disease progression was attenuated versus C57Bl/6 controls. By means of in-depth biomechanical and physiological testing of isolated aortic rings, we can support the following 8 disease mechanisms of aortic stiffening as therapeutic target in arterial ageing: (1) contraction-independent aortic stiffening, (2) endothelial dysfunction, (3) heightened α1-adrenoreceptor mediated vascular smooth muscle cell (VSMC) contractility, (4) aberrant voltage-gated calcium channel (VGCC) signalling, (5) altered store operated calcium entry-mediated signalling, (6) VSMC intracellular calcium handling, (7) focal adhesions in mechanotransduction, and (8) VSMC phenotypic modulation. Therefore, we believe that the phenotypic evidence in support of these disease mechanisms will contribute to the development of an arterial stiffness-targeting treatment for arterial ageing and uncontrolled hypertension. Furthermore, from our comprehensive ex vivo biomechanical studies, we learned that the effect of vasoactive signalling pathways on aortic stiffening is a complex sum of VSMC contraction, VSMC adhesion, and extracellular matrix components, underlining the importance of studying aortic function using multiple method. This work thus also contributes to the knowledge on how to study aorta biomechanical behaviour in an experimental ex vivo setting.
Aantal pagina's: 225
Jaar van publicatie:2022
Trefwoorden:Doctoral thesis
Toegankelijkheid:Open