Background: Arterial stiffness is associated with cognitive decline and dementia; however, the precise mechanisms by which it affects the brain remain unclear. Methods and Results: Using a mouse model based on carotid calcification this study characterized mechanisms that could contribute to brain degeneration due to arterial stiffness. At 2 weeks postcalcification, carotid stiffness attenuated resting cerebral blood flow in several brain regions including the perirhinal/entorhinal cortex, hippocampus, and thalamus, determined by autoradiography ( P <0.05). Carotid calcification impaired cerebral autoregulation and diminished cerebral blood flow responses to neuronal activity and to acetylcholine, examined by laser Doppler flowmetry ( P <0.05, P <0.01). Carotid stiffness significantly affected spatial memory at 3 weeks ( P <0.05), but not at 2 weeks, suggesting that cerebrovascular impairments precede cognitive dysfunction. In line with the endothelial deficits, carotid stiffness led to increased blood‐brain barrier permeability in the hippocampus ( P <0.01). This region also exhibited reductions in vessel number containing collagen IV ( P <0.01), as did the somatosensory cortex ( P <0.05). No evidence of cerebral microhemorrhages was present. Carotid stiffness did not affect the production of mouse amyloid‐β (Aβ) or tau phosphorylation, although it led to a modest increase in the Aβ40/Aβ42 ratio in frontal cortex ( P <0.01). Conclusions: These findings suggest that carotid stiffness alters brain microcirculation and increases blood‐brain barrier permeability associated with cognitive impairments. Therefore, arterial stiffness should be considered a relevant target to protect the brain and prevent cognitive dysfunctions.

Following the discovery of the vasorelaxant properties of nitric oxide (NO) by Furchgott and Ignarro, the finding by Bredt and coll. of a constitutively expressed NO synthase in neurons (nNOS) led to the presumption that neuronal NO may control cerebrovascular functions. Consequently, numerous studies have sought to determine whether neuraly-derived NO is involved in the regulation of cerebral blood flow (CBF). Anatomically, axons, dendrites, or somata of NO neurons have been found to contact the basement membrane of blood vessels or perivascular astrocytes in all segments of the cortical microcirculation. Functionally, various experimental approaches support a role of neuronal NO in the maintenance of resting CBF as well as in the vascular response to neuronal activity. Since decades, it has been assumed that neuronal NO simply diffuses to the local blood vessels and produce vasodilation through a cGMP-PKG dependent mechanism. However, NO is not the sole mediator of vasodilation in the cerebral microcirculation and is known to interact with a myriad of signaling pathways also involved in vascular control. In addition, cerebrovascular regulation is the result of a complex orchestration between all components of the neurovascular unit (i.e., neuronal, glial, and vascular cells) also known to produce NO. In this review article, the role of NO interneuron in the regulation of cortical microcirculation will be discussed in the context of the neurovascular unit.

Hypertension is the most prevalent and modifiable risk factor for stroke, vascular cognitive impairment, and Alzheimer’s disease. However, the mechanistic link between hypertension and neurodegenerative diseases remains to be understood. Recent evidence indicates that inflammation is a common pathophysiological trait for both hypertension and neurodegenerative diseases. Low-grade chronic inflammation at the systemic and central nervous system levels is now recognized to contribute to the physiopathology of hypertension. This review speculates that inflammation represents a mediator between hypertension and neurodegenerative diseases, either by a decrease in cerebral blood flow or a disruption of the blood–brain barrier which will, in turn, let inflammatory cells and neurotoxic molecules enter the brain parenchyma. This may impact brain functions including cognition and contribute to neurodegenerative diseases. This review will thus discuss the relationship between hypertension, systemic inflammation, cerebrovascular functions, neuroinflammation, and brain dysfunctions. The potential clinical future of immunotherapies against hypertension and associated cerebrovascular risks will also be presented.

Background: Arterial stiffness has been identified as an important risk factor for cognitive decline. However, its effects on the brain's health are unknown, and there is no animal model available to study the precise impact of arterial stiffness on the brain. Therefore, the objective of the study was to develop and characterize a new model specific to arterial stiffness in order to study its effects on the brain. Methods and Results: Calcium chloride (CaCl ₂ ) was applied to carotid arteries of mice, inducing an increase in collagen distribution and intima–media thickness, a fragmentation of elastin, a decrease in arterial compliance and distensibility, and an increase in cerebral blood flow pulsatility (n=3 to 11). Calcium deposits were only present at the site of CaCl ₂ application, and there was no increase in systemic blood pressure or change in vessel radius making this model specific for arterial stiffness. The effects of carotid stiffness were then assessed in the brain. Carotid calcification induced an increase in the production of cerebral superoxide anion and neurodegeneration, detected with F luoro‐ J ade B staining, in the hippocampus (n=3 to 5), a key region for memory and cognition. Conclusions: A new model of arterial stiffness based on carotid calcification was developed and characterized. This new model meets all the characteristics of arterial stiffness, and its specificity allows the study of the effects of arterial stiffness on the brain.