From cyclic stretch to vascular ageing : a comprehensive analysis of aortic tissue mechanics
The aorta, a large elastic artery, serves as the primary conduit for blood exiting the heart, propelling oxygenated blood to every organ and tissue throughout the body. Its ability to adapt to the rhythmic ebb and flow of cardiac output is a testament to the marvels of nature's design. However, when this delicate equilibrium is perturbed, as seen as during progression of diseases such as aortic aneurysms, aortic dissection or atherosclerosis, gaining insight in the aorta's biomechanical characteristics becomes paramount in understanding the pathophysiology of such conditions and guiding clinical decision-making. In Part I, we aimed to unravel the interplay between cyclic stretch and aortic viscoelasticity. These experiments were performed using an in-house developed ex vivo setup to study arterial mechanics. We demonstrated that increased pulsatility (i.e. cyclic stretch amplitude) decreases arterial stiffness (chapter 3). More so, an acute bout of high cyclic stretch amplitude was shown to reduce smooth muscle cell-mediated arterial stiffness, suggesting that cyclic stretch acts on a cellular component (chapter 4). Lastly, regional differences in smooth muscle cell contractility explained differences in the effect of cyclic stretch on arterial viscoelasticity (chapter 5). This data displayed the intricate relationship between cyclic stretch, smooth muscle cell function and arterial mechanics. The central theme of Part II is “Vascular ageing”. As the world’s aged population grows considerably, research on ageing has become an ever-important field of science. An increase in the number of aged individuals is expected to be accompanied by a parallel increase in the incidence of cardiovascular disease (CVD). Further research to determine preventive strategies and their underlying molecular mechanisms is an unmet need in order to reduce the health care burden of CVD. In Part II, we demonstrated how spontaneous ageing affects the murine aorta which was measured using in vivo and ex vivo techniques (chapter 6). This study additionally revealed that readouts of vascular ageing differed considerably between different methods, highlighting the need for harmonisation on measuring arterial mechanics. Next, we aimed to determine whether such ageing-induced changes could be attenuated by pharmacological intervention. Interestingly, empagliflozin, a drug used in the treatment of diabetes mellitus type 2, reduced ageing-induced arterial stiffening in the absence of hyperglycaemia (chapter 7). This indicates arterial stiffness can be pharmacologically modulated, which is promising in the context of attenuating (early) vascular ageing. However, no universal mechanism was identified for the anti-geronic effect of empagliflozin. Finally, we investigated the role of calciprotein particles, which are small, circulating, nano-sized calcium-phosphate containing protein complexes, as potential inducers of vascular ageing. Calciprotein particles were found to induce arterial stiffening, ex vivo, induce endothelial cell dysfunction and inhibit vascular cell autophagy, which are hallmarks of vascular ageing. This data unveils calciprotein particles as a potential, novel, risk factor for developing cardiovascular disease and perhaps even as overall biomarkers for cardiovascular ageing. Future research should investigate how the detrimental effect(s) of calciprotein particles on the cardiovascular system can be attenuated. This would lead to novel insights in decreasing the cardiovascular comorbidities as seen as with ageing. Overall, vascular cells, and especially smooth muscle cells, determine the biomechanical properties of the aortic and play an important role in maintaining normal vascular homeostasis. These data generate novel research questions about the “mechanosensing” properties of cells in arterial tissue both physiologically as well as in disease. How do cells sense mechanical cues? Does their sensing change during ageing, for example? Is targeting “mechanosensing” an interesting approach in treating cardiovascular disease? Can we reverse changes induced by vascular ageing or can we only slow down its progression? Understanding how vascular cells modulate aortic mechanics in physiological conditions provides crucial information when to develop therapies that specifically aim to reduce arterial stiffening in disease.
Antwerpen : Universiteit Antwerpen, Faculteit Geneeskunde en Gezondheidswetenschappen , 2024
277 p.
Supervisor: Guns, Pieter-Jan [Supervisor]
Supervisor: Martinet, Wim [Supervisor]
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From hit to lead: inducing basal autophagy for treating cardiovascular diseases.
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Publications with a UAntwerp address
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Creation 29.02.2024
Last edited 07.03.2024
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