Impact of arterial stiffness on cerebrovascular function: a review of evidence from humans and preclincal models

Abstract

With advancing age, the cerebral vasculature becomes dysfunctional, and this dysfunction is associated with cognitive decline. However, the initiating cause of these age-related cerebrovascular impairments remains incompletely understood. A characteristic feature of the aging vasculature is the increase in stiffness of the large elastic arteries. This increase in arterial stiffness is associated with elevated pulse pressure and blood flow pulsatility in the cerebral vasculature. Evidence from both humans and rodents supports that increases in large elastic artery stiffness are associated with cerebrovascular impairments. These impacts on cerebrovascular function are wide-ranging and include reductions in global and regional cerebral blood flow, cerebral small vessel disease, endothelial cell dysfunction, and impaired perivascular clearance. Furthermore, recent findings suggest that the relationship between arterial stiffness and cerebrovascular function may be influenced by genetics, specifically APOE and NOTCH genotypes. Given the strength of the evidence that age-related increases in arterial stiffness have deleterious impacts on the brain, interventions that target arterial stiffness are needed. The purpose of this review is to summarize the evidence from human and rodent studies, supporting the role of increased arterial stiffness in age-related cerebrovascular impairments.

Keywords: aging; arterial stiffness; blood pressure; cerebral blood flow; cerebrovascular.

Figure 1.

Changes to large elastic arteries with advancing age. At young ages, large arteries are relatively compliant with a high ratio of elastin to collagen. At older ages, large arteries become stiffer due to a reduced elastin content, fragmentation of elastin, increased collagen content, and cross linking of collagen. Purple, collagen; green, elastin; pink, vascular smooth muscle cells. Figure created with a licensed version of BioRender.com.

Figure 2.

Impact of increased large elastic artery stiffness on the cerebral vasculature. Age-related increases in large artery stiffness will lead to elevated pulse pressure, and this higher pulse pressure puts greater circumferential stress on the wall of cerebral blood vessels. The resulting stretch of the vascular cells can lead to a proinflammatory and prooxidant environment associated with mitochondrial and DNA damage. This vascular dysfunction leads to reduced cerebral perfusion and, ultimately, to cognitive impairment. Figure created with a licensed version of BioRender.com.

Figure 3.

Impact of increased large artery stiffness on cerebrovascular function in humans and rodents. Human/rodent symbols indicate whether the current evidence available for each function is from human and/or rodent studies. Figure created with a licensed version of BioRender.com.

Figure 4.

Experimental models for studying the impact of arterial stiffness. With older age in both humans and rodents, there is an increase in stiffness of the large elastic arteries and cerebral arteries, as well as an increase in pulse pressure. Rodent models of stiffer large arteries and increased cerebral pulse pressure mimic many of these effects of aging but can be studied at young ages, thus eliminating other age-related confounding effects. Eln^+/−, elastin heterozygote knockout mouse; green check mark, the feature is present in the model; red X, the feature is not present in the model; ?, presence of the feature is unknown; N/A, model specific to pulse pressure. Figure created with a licensed version of BioRender.com.

Figure 5.

Hypothetic framework by which APOEε4 genotype modulates the consequences of arterial stiffness and blood pressure. A: current evidence suggests that carriers of the APOEε4 genotype have a stronger relationship between increased large artery stiffness (or high blood pressure) with cerebrovascular and cognitive impairment. B: typical correlations were found between aortic stiffness (measured by pulse wave velocity) and cognitive function (59) or cerebral blood flow (104) in APOEε4 carriers and noncarriers. Figure created with a licensed version of BioRender.com.

Figure 6.

Cerebral artery pulsatility and the periarterial space: comparison of compliant and stiff cerebral artery and arterioles. The changes with each pulse to diameter (vessel wall pulsatility, distension) and blood flow/pressure are shown. Arterial stiffness is associated with enlarged periarterial spaces and reduced perivascular flow. Figure created with a licensed version of BioRender.com.