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Assessing the Causes of Aortic Stiffening in Aged Mice


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Posted 24 June 2022 - 07:11 PM


Aortic stiffness occurs with age, and produces raised blood pressure, hypertension, by sabotaging the usual feedback mechanisms that control blood pressure. Hypertension in turn results in structural damage to delicate tissues throughout the body, as well as producing further biochemical changes that encourage ventricular hypertrophy, among other forms of dysfunction. It causes enough harm that control of blood pressure can meaningfully reduce mortality even without addressing underlying causes of degenerative aging.

Why do arteries stiffen with age? As today's open access paper discusses, this is in part a complex set of changes in the extracellular matrix of blood vessel walls, and in part dysfunction of the smooth muscle cells responsible for constriction and dilation of blood vessels. In the absence of ways to fully reverse one or other of these issues, it remains unclear as to how much of the problem is caused by each of these two contributions, but we can hope that this will change in the near future, given greater investment in research into the mechanisms of aging.

The structure and composition of the extracellular matrix defines the physical properties of a tissue, such as elasticity. With age, elastin laid down in youth becomes damaged and disordered, while other macromolecules that should slide past one another become cross-linked together by persistent advanced glycation end-products such as glucosepane. Meanwhile, inflammatory signaling and other forms of age-related biochemical dysfunction cause impairment in vascular smooth muscle, a failure to respond appropriately to signals to contract or dilate blood vessels.

Progressive aortic stiffness in aging C57Bl/6 mice displays altered contractile behaviour and extracellular matrix changes

As human life expectancy continues to grow, the incidence of age-related cardiovascular diseases (CVD) rises. CVD has long since become the leading cause of death, resulting in an estimated 17.9 million deaths each year (i.e., 30% of global death). Arterial stiffening - defined as the impaired capacity of the large elastic arteries to smoothen pulsatile blood flow - results in increased cardiac afterload, reduced coronary perfusion pressure, and pulsatile strain on the microcirculation. As such, arterial stiffness has gained much recognition as a hallmark and independent predictor of CVD.

Elastic arteries display a distinctly non-linear stiffness-pressure relation, with a limited increase in stiffness in the physiological pressure range but exponential increase at high distending pressure. Interestingly, despite pronounced variation in structural properties and vessel size across species, elastic modulus at mean physiological pressure is highly conserved across all vertebrate and invertebrate species with a closed circulatory system, suggesting strong evolutionary pressure.

In the present study, a longitudinal cardiovascular characterization of spontaneously (i.e., age-dependent) ageing C57Bl/6 mice is presented to establish the temporal relation of aortic stiffness to associated CVD, i.e., cardiac hypertrophy and peripheral hypertension. Furthermore, an in-depth physiological and biomechanical investigation of the isolated ex vivo thoracic aorta was employed to identify the key mechanisms of spontaneous arterial stiffening. We demonstrated that aortic stiffening precedes peripheral blood pressure alterations and left ventricular hypertrophy in spontaneously ageing C57Bl/6 mice, underlining the importance of implementing arterial stiffness measurement as an early marker of cardiovascular ageing in standard cardiovascular care.

Contraction-independent stiffening (due to extracellular matrix changes) is pressure-dependent. Contraction-dependent aortic stiffening develops through heightened α1-adrenergic contractility, aberrant voltage-gated calcium channel function, and altered vascular smooth muscle cell calcium handling. Endothelial dysfunction is limited to a modest decrease in sensitivity to acetylcholine-induced relaxation with age. Our findings demonstrate that progressive arterial stiffening in C57Bl/6 mice precedes associated cardiovascular disease. Aortic aging is due to changes in extracellular matrix and vascular smooth muscle cell signalling, and not to altered endothelial function.


View the full article at FightAging




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