Large artery stiffness and brain health: insights from animal models

Abstract

There are no effective treatments available to halt or reverse the progression of age-related cognitive decline and Alzheimer's disease. Thus, there is an urgent need to understand the underlying mechanisms of disease etiology and progression to identify novel therapeutic targets. Age-related changes to the vasculature, particularly increases in stiffness of the large elastic arteries, are now recognized as important contributors to brain aging. There is a growing body of evidence for an association between greater large artery stiffness and cognitive impairment among both healthy older adults and patients with Alzheimer's disease. However, studies in humans are limited to only correlative evidence, whereas animal models allow researchers to explore the causative mechanisms linking arterial stiffness to neurocognitive dysfunction and disease. Recently, several rodent models of direct modulation of large artery stiffness and the consequent effects on the brain have been reported. Common outcomes among these models have emerged, including evidence that greater large artery stiffness causes cerebrovascular dysfunction associated with increased oxidative stress and inflammatory signaling. The purpose of this mini-review is to highlight the recent findings associating large artery stiffness with deleterious brain outcomes, with a specific focus on causative evidence obtained from animal models. We will also discuss the gaps in knowledge that remain in our understanding of how large artery stiffness affects brain function and disease outcomes.

Keywords: aging; cerebrovascular; cognitive dysfunction; endothelial function; vascular stiffness.

Figure 1.

Hypothesized mechanism for cerebrovascular impairment caused by greater large artery stiffness. Top: the distension of the arterial wall dampens the pulse wave as it travels through the large arteries. When large arteries become less compliant (more stiff), as with advancing age, this dampening of pulse pressure is reduced. Middle: the highest mean blood pressure and widest pulse pressure are found in the large elastic and muscular arteries. Moving through the arterial tree, the mean blood pressure and pulse pressure are diminished to the extent that the pressure is constant (not pulsatile) in capillaries. However, with increased stiffness of the large arteries, the pulse pressure is widened throughout the arterial tree, including greater pulse pressure in small arteries, arterioles, and capillaries. Bottom: the small arteries, arterioles, and capillaries in the brain are thin-walled and do not have the structure to cope with the increased pulse pressure that results from greater large artery stiffness. This increased pulse pressure in the cerebral circulation potentially leads to cerebrovascular damage and dysfunction. Created with Biorender with permission.

Figure 2.

Summary of findings from studies of rodent models of greater large artery stiffness and brain-related outcomes. Rodent models of greater large artery stiffness include transgenic mice (Eln and Fbn1) and induced carotid calcification in mice. In these models, the greater large artery stiffness results in greater cerebral oxidative stress and inflammation, cerebral artery endothelial dysfunction, impaired cerebral blood flow, and neurodegeneration. Increased large artery stiffness also leads to cognitive impairment in mice, and it is assumed that this cognitive impairment results in the cerebral vascular and cellular changes. Created with Biorender with permission.