Functional vascular contributions to cognitive impairment and dementia: mechanisms and consequences of cerebral autoregulatory dysfunction, endothelial impairment, and neurovascular uncoupling in aging

Abstract

Increasing evidence from epidemiological, clinical and experimental studies indicate that age-related cerebromicrovascular dysfunction and microcirculatory damage play critical roles in the pathogenesis of many types of dementia in the elderly, including Alzheimer's disease. Understanding and targeting the age-related pathophysiological mechanisms that underlie vascular contributions to cognitive impairment and dementia (VCID) are expected to have a major role in preserving brain health in older individuals. Maintenance of cerebral perfusion, protecting the microcirculation from high pressure-induced damage and moment-to-moment adjustment of regional oxygen and nutrient supply to changes in demand are prerequisites for the prevention of cerebral ischemia and neuronal dysfunction. This overview discusses age-related alterations in three main regulatory paradigms involved in the regulation of cerebral blood flow (CBF): cerebral autoregulation/myogenic constriction, endothelium-dependent vasomotor function, and neurovascular coupling responses responsible for functional hyperemia. The pathophysiological consequences of cerebral microvascular dysregulation in aging are explored, including blood-brain barrier disruption, neuroinflammation, exacerbation of neurodegeneration, development of cerebral microhemorrhages, microvascular rarefaction, and ischemic neuronal dysfunction and damage. Due to the widespread attention that VCID has captured in recent years, the evidence for the causal role of cerebral microvascular dysregulation in cognitive decline is critically examined.

Keywords: Alzheimer’s disease; blood-brain barrier; cerebral circulation; cerebrovascular; functional hyperemia; geroscience; microcirculation; myogenic constriction; neurovascular coupling; senescence; stroke; vascular aging.

Fig. 1.

Aging impairs adaptation of cerebral blood flow (CBF) autoregulation to hypertension. A: scheme depicting that under normal conditions autoregulation of CBF maintains a nearly constant blood flow when perfusion pressure changes. This is ensured by pressure-induced myogenic constriction of the cerebral arteries (C), a homeostatic mechanism that rapidly adjust vascular resistance to changes in perfusion pressure. The significant increases in the resistance of proximal arteries also assure that increased arterial pressure does not penetrate the distal portion of the microcirculation and cause damage to the thin-walled arteriolar and capillary microvessels in the brain (103, 147). In young organisms in hypertension the myogenic constriction of cerebral arteries is enhanced (C) and the range of cerebrovascular autoregulation is extended (A), which represent functional adaptation of these vessels to higher systemic blood pressure, optimizing tissue perfusion and protecting the cerebral microcirculation. Aged cerebral arteries do not exhibit a hypertension-induced adaptive increase in myogenic constriction (D) and cerebrovascular autoregulatory dysfunction is manifested (B) (271, 281). E and F: proposed scheme showing that in young organisms activation of a 20-hydroxyeicosatrienoic-acid (20-HETE)/transient receptor potential cation channel (TRPC)-dependent pathway underlies functional adaptation of cerebral arteries to hypertension (blue arrows) and that this adaptive response is dysfunctional in aging (red arrows). Accordingly, in smooth muscle cells within the wall of young cerebral arteries (E), high pressure-induced mechanical stress leads to the activation of arachidonic acid metabolism (AA) by phospholipase A₂ (PLA₂), and upregulation of the 20-HETE producing CYP450 isoforms. The resulting increased production of the vasoconstrictor eicosanoid 20-HETE activates TRPC6 channels, resulting in increases in vascular smooth muscle Ca²⁺ concentration and subsequent sustained myogenic constriction (281). 20-HETE also blocks the activation of the hyperpolarizing Ca²⁺ activated potassium (BK_Ca) channels on vascular smooth muscle cells, which contributes to the increased pressure-induced activation of voltage-dependent L-type Ca²⁺ (L_Ca) channels and enhanced myogenic constriction. F: in aged cerebral arteries the functional adaptation to hypertension mediated by activation of the 20-HETE/TRPC-dependent pathway is impaired (red arrows).

Fig. 2.

Age-related autoregulatory dysfunction exacerbates hypertension-induced cerebromicrovascular injury. Shown is a schematic illustration of the likely consequences of autoregulatory dysfunction in the aging brain. The model proposed implies that in healthy young organisms pressure-induced myogenic constriction of the proximal cerebral arteries acts as a critical homeostatic mechanism that assures that increased arterial pressure does not penetrate the distal portion of the microcirculation and cause damage to the thin-walled arteriolar and capillary microvessels in the brain (103, 147). In aging, proximal resistance arteries lose their capability to adapt to hypertension with an enhanced pressure-induced constriction, which leads to a mismatch in perfusion pressure and segmental vascular resistance (resistance is inversely related to the 4th power of vessel radius). Lack of proper autoregulatory protection in aging likely allows high blood pressure to penetrate the vulnerable downstream portion of the cerebral microcirculation. The hemodynamic burden exacerbates age-related disruption of the blood-brain barrier (BBB), leading to extravasation of plasma factors, which promote neuroinflammation (e.g., activation of microglia by IgG via the IgG Fc receptors). Microglia-derived proinflammatory cytokines, chemokines, proteases [i.e., matrix metalloproteinase (MMP)] and reactive oxygen species (ROS) promote neuronal damage (273, 281). In addition, the increased microvascular pressure activates matrix metalloproteinases in the vascular wall in a redox-sensitive manner, contributing to the development of microhemorrhages (276). The age-related autoregulatory dysfunction and its consequences may also contribute to the dysfunction of the glymphatic system (128, 148), and the development of age-related vascular rarefaction (281). We posit that exacerbation of neuroinflammation, cerebral microhemorrhages, glymphatics dysfunction and/or microvascular rarefaction are causally linked to hypertension-induced cognitive impairment in aging (85, 210, 285) and contribute to the increased prevalence of Alzheimer’s disease in hypertensive elderly individuals. Bottom: representative images showing cerebral microhemorrhages (brown lesions after diaminobenzidine-hematoxylin staining, scale bar = 200 μm) in the brain of aged (24 mo old) hypertensive mice, which associate with autoregulatory dysfunction. Note that most hypertension-induced microhemorrhages are located in the cortical and subcortical region. Hypertension was induced in the mice by treatment with angiotensin II and the nitric oxide synthase inhibitor nitro-l-arginine methyl ester (l-NAME) (279).

Fig. 3.

Aging impairs neurovascular coupling responses: potential role of insulin-like growth factor-1 (IGF-1). Shown is a schematic illustration of age-related alterations in glio-endothelial coupling mechanisms, which are responsible for impaired functional hyperemia in the elderly. Accordingly, under normal conditions astrocytes mediate the interaction between neurons and vascular cells by physically connecting neuronal synapses to cerebrovascular smooth muscle wall. Glutamate released from active excitatory synapses triggers a calcium wave that travels through the astrocyte and reaches the end-feet wrapped around the vessel wall. The glutamate-induced calcium surge activates CYP450- and cyclooxygenase (COX)-mediated production of vasodilator eicosanoids [epoxyeicosatrienoic acids (EETs) and prostaglandins, respectively] and promotes activation of ATP release machinery. Astrocyte-derived ATP promotes endothelial release of vasodilator nitric oxide (NO) via activation of P2Y1 receptors (276). The model predicts that aging impairs all of these mechanisms involved in glio-vascular coupling responses. Of particular importance is the purinergic endothelial NO-mediated pathway, which may be affected by both endothelial oxidative stress [increased ROS production by NOX oxidases (195) and mitochondrial sources] and astrocyte-derived ROS production. The known age-related changes are showed using red arrows. Age-related decreases in levels of circulating IGF-1 is one of the most important endocrine changes accompanying aging. On the basis of evidence obtained in IGF-1-deficient mouse models of aging (275) the model predicts that age-related decline in IGF-1 impairs both astrocyte function and endothelium-mediated mechanisms of functional hyperemia. Note, that the scheme does not include IGF-1 deficiency-induced potential alterations in neuronal release of vasodilator substances and/or the role of IGF-1-related changes in astrocyte-mediated capillary dilation.

Fig. 4.

Functional vascular contributions to cognitive impairment and dementia in aging. The schematic representation illustrates the interrelated microvascular mechanisms that contribute to age-related cognitive decline. The model highlights that age-related IGF-1 deficiency compromises the neurovascular unit, impairing the function of astrocytes, endothelial cells and smooth muscle cells. The resulting endothelial dysfunction and decreased NO bioavailability, increased oxidative stress, and/or dysregulation of astrocytic mediators contribute to neurovascular uncoupling, which impairs cognitive function due to inadequate supply of oxygen and nutrients to active brain regions. Age-related impairment of microvascular homeostasis, including alterations of myogenic autoregulatory mechanisms, renders the aged brain more susceptible to damage induced by comorbid conditions such as hypertension. In particular, the model predicts that impaired myogenic adaptation to hypertension promotes both the pathogenesis of cerebral microhemorrhages and blood-brain-barrier disruption, contributing to neuronal damage and cognitive decline. Aging and age-related IGF-1 deficiency also promote structural remodeling of the cerebral microcirculation, including microvascular rarefaction, contributing to an age-related decline in cerebral blood flow. They also promote structural maladaptation to hypertension, increasing microvascular fragility. Additionally, age-related microvascular proinflammatory alterations, impairment of vascular clearance of toxic waste products (such as Aβ) and metabolic by-products from the brain parenchyma and impaired trophic function of the microvascular endothelium that regulate stem cell self-renewal and differentiation in neurogenic niches could be implicated in impaired cognitive function.