As previously mentioned, brain vascular resistance is very low. Thus small cerebral arterial vessels are exposed to the high-pressure fluctuations that exist in the carotid and cerebral arteries [73]. Any increase in systemic pulse pressure may induce cerebrovascular damage [37]. Indeed, increase in pulsatility and resistance indexes of the mean cerebral artery (MCA), two indexes that reflect downstream increase in vascular resistance, are related to increase in aortic stiffness [74]. Furthermore, arterial stiffening with aging increases carotid flow augmentation that may explain the increase in CBF fluctuations [75]. Several studies establish a link between peripheral arterial stiffness and brain microvascular disease such as cerebral small vessel disease, white matter changes or cognitive function in older individuals [76–78], hypertensive [79, 80] and diabetic patients [81, 82]. More recently, it has been reported that CBF pulsatility is independently associated with central hemodynamics and that higher pulsatility of CBF was positively correlated with the greater total volume of white matter hyperintensity [83]. Finally, leukoaraiosis is strongly associated with cerebral arterial pulsatility that is strongly dependent on aortic pulsatility and large artery stiffness [84]. Thus physiopathological conditions characterized by an increase in peripheral arteries stiffness are associated with brain damages. This may suggest that peripheral arteries stiffness may impact on cerebral arterioles structure and function. It has already been reported that increases in pulse pressure may play a role on cerebral arterioles structure and mechanics [85, 86]. Finally, in a recent study, it was reported that experimental stiffening of the carotid artery of young mice using CaCl₂ application, led to collagen synthesis, fragmentation of elastin filaments, leading to an increase in CBF pulsatility and intracranial cerebrovascular damage and neuronal loss [87]. This is the first demonstration that stiffening of the carotid artery alone damages the brain.

Cerebral arterioles undergo alteration in wall structure and dynamics as well as in function in conditions associated with an increase in aortic stiffness such as aging, hypertension, and chronic renal failure. However, despite similar impact on aortic stiffness as measured by PWV, structure and dynamics of cerebral arterioles differ in these circumstances. Considering aging, one study revealed that in 24- to 27-month-old Fisher rats, pial arteriolar wall underwent atrophy with the loss of nearly half of the volume occupied by VSMC; the wall became stiffer; the passive internal diameter of deactivated (Ca²⁺-free experimental conditions) arterioles became smaller [88]. Furthermore, collaterals branching from the MCA and anterior cerebral arteries are altered in old mice, evidenced by a rarefaction collateral number, a reduction in diameter, and an increased tortuosity consistent with a sixfold increment of collateral resistance [89]. In human, it has been reported an association between arterial stiffness evaluated by the brachial-ankle PWV and cerebrovascular resistance in the elderly [90]. Thus, peripheral artery stiffness influences cerebral circulation in this population. However, the study does not allow to determine if the increase in cerebrovascular resistance is consecutive to structural or functional alterations of cerebral arteries and arterioles. However, in another study performed in middle-aged and older individuals, arterial wall stiffening in large arterial beds is associated with retinal arteriolar narrowing indicating that large artery stiffness may impact on cerebral vasculature structure [91]. Postmortem human posterior cerebral arteries (~2.3 mm) were compared in 6 young (~42 years of age) and 6 aged (~70 years of age) adults with severe cardiovascular disorders: aging was associated with a thicker intima and media, a loss of VSMC but an increase in collagen, a severe stiffening and concomitant elastin fiber dysfunction with possible fragmentation and reorganization [92]. In this study however, it may be difficult to differentiate effects of aging from effects of severe cardiovascular disorders.

During chronic hypertension, basilar arteries, posterior cerebral arteries, and the MCA (>200 μm) stiffen in hypertensive rats [93–96]. In contrast, cerebral arteries (>150 μm) and arterioles (<70 μm) distensibility has been reported to increase in rat and mouse models of hypertension [97, 98] and mice deficient in superoxide dismutase [99]. Arterial wall hypertrophy accompanied both hypertension and atherosclerosis and eutrophic inward remodelling was observed in some models of hypertension in rats [100, 101].

Structure and mechanics of cerebral arterioles were not altered in a model of chronic kidney disease in the mice. In contrast endothelium-dependent relaxation was decreased in mice with chronic renal failure [102]. In human, chronic kidney disease is associated with an increase in intracranial arteries calcification. Furthermore calcification of intracranial arteries is associated with a higher risk of stroke and with a greater postischemic stroke mortality and vascular events [103]. However, intracranial arteries calcification is also associated with aortic atherosclerosis and may thus be an indication of intracranial arteries atherosclerosis rather than intracranial arteries stiffness [104]. Indeed, we have no indications on the impact of calcification on intracranial arteries stiffness.

Thus it is difficult to conclude regarding the impact of peripheral arteries stiffness and structure and function of cerebral arterioles. We might expect that an increase in aortic stiffness would lead to similar cerebral arteriolar alterations regardless of the conditions associated with this increase (i.e., aging, hypertension or chronic kidney disease). However, it is worth noting that in these three conditions, cerebral arteriolar dilatation may be impaired following either a decrease in cerebral arteriolar distensibility in aging, remodelling leading to a decrease in internal diameter in hypertension or endothelial dysfunction in chronic kidney disease. This may lead to cerebral hypoperfusion by increasing the lower limit of CBF autoregulation.

Peripheral arteries stiffness by increasing pulse pressure may impact on cerebral arteriolar endothelial function. As previously mentioned, endothelium-dependent relaxation is impaired in chronic kidney disease [102]. However, there is no indication that this is related to an increase in aortic stiffness. It has already been reported that pulse pressure may impair endothelial function in hypertensive rats [105]. We should acknowledge that the endothelium is under a pulsatile mechanical stress. Some studies have tested the impact of such a stress on endothelial function in vitro but without targeting the cerebrovascular endothelium. Nonetheless, these studies show that a cyclic mechanical stretch of 12 % (1 Hz) imposed to human umbilical vein endothelial cells (HUVEC) grown on a flexible membrane led to the increase in reactive oxygen species (ROS) at 30 min followed by a rise in PKC activity and ICAM-1 expression after 24 h [106, 107]. Activation of NADPH oxidase (p22phox subunit) was shown to be responsible for this increased inflammatory response including a NFκB-dependent TNFα production in response to a 6 % stretch at 1 Hz for 6 h [108] as well as the rise in MMP-2 and -14 activities [109], which are considered in vivo to be necessary for arterial wall remodelling. In addition, cyclic stretch induces a sequential activation of PKC isoform (α and ε) that contribute to Raf/ERK1/2 activation, and PKC-ε appears to play a key role in endothelial adaptation to hemodynamic environment [107]. These experimental data, although only collected in cultured endothelial cells, support in vivo integrative data demonstrating a direct relationship between cerebral artery compliance and endothelial function [110]. At least one study reports a correlation between conduit vessel stiffness and endothelial function. However, the study does not allow to conclude if the increase in conduit vessel stiffness is a cause or a consequence of endothelial dysfunction [111].

The role of endothelial dysfunction in chronic and/or acute CBF maladaptation is pre-supposed but difficult to experimentally isolate considering the multiple impact of the function of the endothelium on arterial diameter, wall structure, permeability, and transport of molecules as well as migration of blood cells through the wall [38, 112, 113]. Aging may offer some opportunities to evaluate impact of endothelial dysfunction on CBF maladaptation.

Firstly, the gradual decline of the endothelial cell function characterizes cerebral vascular aging [38, 114, 115]. Infusion of l-arginine (eNOS substrate) increases less blood flow in the MCA of older compared to younger human subjects [116] suggesting impaired eNOS enzymatic activity. Circulating levels of asymmetric dimethylarginine (ADMA), the endogenous eNOS inhibitor, increase with age in humans and could be an independent risk factor of ischemic stroke [117–119]. In Alzheimer’s disease patients, plasma levels of ADMA increase while those of NO decrease [120]. ADMA induce endothelial dysfunction of cerebral arteries [121] and decrease CBF in healthy humans [122]. Yet, one study reported that ADMA concentration in CSF decreases with age [123]. In addition, a rapid inactivation of NO by ROS could attenuate cerebral endothelial function [124–126]. Secondly, aging is associated with a gradual stiffening of the carotid arteries [127], transmitting the pulsations of peripheral flow to the brain microcirculation that favors pulse wave encephalopathy [20]. Thirdly and most importantly, preclinical studies suggest that endothelial dysfunction and alteration in the biomechanical properties of the vascular wall synergize in cerebral arteries [110] (Fig. 7.2). Hence, carotid stenosis [128] and endothelial dysfunction [128–130] may perturb cerebral artery hemodynamics and contribute to the decrease in cerebral capillary density [89], a phenomena that is already detectable during the fifth decade in healthy humans [131]. Because CBF is tightly coupled to neuronal metabolic demand [132–135], the development of chronic brain hypoperfusion together with the increase in intercapillary distances (for review, [136]) promotes progressive hypometabolism [137], chronic BBB inflammation, and leakiness [138], at a stage where brain cell dysfunction is irreversible. Age-related cognitive decline may therefore be strongly influenced by cerebrovascular dysfunctions, a defect that may be magnified by the structural changes of the cerebral artery walls (for review [129, 134, 139–141]).

We pose that defects (functional, mechanical, and structural) in blood flow to the brain leads to a disturbed brain metabolism that would generate neuroglial energy crisis and neuronal loss, together with the accumulation of cytotoxic by-products of brain activity [139, 140, 142]. Consequently, chronic suboptimal brain perfusion would impair cognition [129, 139]. In support of this contention, resting CBF gradually declines in most areas of the brain between the age of 21 and 81 years in healthy volunteers [132]. In addition, oxygen extraction fraction increases in the lower perfused area only as previously shown by others [143, 144]. These brain areas are vulnerable to neuronal degeneration [145] and increased oxygen extraction fraction is a sign of poor oxygen delivery to neurons, and chronically, contribute to the transition from a healthy to an unhealthy brain [132].