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Riddle DR, editor. Brain Aging: Models, Methods, and Mechanisms. Boca Raton (FL): CRC Press/Taylor & Francis; 2007.

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Brain Aging: Models, Methods, and Mechanisms.

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Chapter 12Regulation of Cerebrovascular Aging

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I. INTRODUCTION

Normal function of virtually all tissues depends on adequate blood flow. As one would expect, deficits in blood flow under basal or stimulated conditions result in diminished metabolic capacity and impairments in function. Importantly, functional deficits in organs and tissues are one of the hallmarks of biological aging but the etiology of these deficits and the potential relationship between alterations in blood flow and the deterioration of tissue function with age remain enigmatic. Empirical and rigorous scientific evidence demonstrates that functional deterioration of many tissues begins in early adulthood and progresses throughout life. Concurrently, there is an increase in tissue pathology, including deposition of insoluble collagen and tissue fibrosis. Despite the structural changes with age, which are generally considered permanent or irreversible, tissue function can be improved even in late ages by several disparate types of interventions, supporting the conclusion that age-related impairments in cellular and tissue function, and perhaps some aspects of aging itself, remain “plastic.” Whether such “plastic” changes depend on increased basal blood flow or the capacity to increase blood flow in response to metabolic challenge remains unknown.

The strong relationship that exists between cellular metabolic capacity and regional blood flow leads to the conclusion that a clear understanding of age-related changes in the regulation of blood flow (including microvascular architecture, plasticity, and vessel reactivity) is essential for understanding the progressive decline in cellular metabolic activity and eventually tissue function with age. Nevertheless, there are a limited number of studies that have considered the potential interrelationships between these variables. The guiding principle of this chapter, and for which there remain insufficient data, is that alterations in the vasculature have the capacity to impact biological aging. These alterations may include, but are not limited to, changes in microvascular density (density of arterioles, arteriolar to arteriolar anastomoses, capillaries, and venules); ultrastructure (cellular components that comprise the vasculature); plasticity (e.g., elaboration, regression, or replacement of microvessels that may occur over days, weeks, or months); and the dynamic regulation of blood flow through the vasculature (e.g., vessel reactivity). Despite the importance of each of these components, historical and technical aspects of research in these areas isolate the scientific disciplines and they are rarely considered a functional unit. This chapter reviews the current state of information in each of these areas as it relates to functional changes within the central nervous system with age.

II. EXPERIMENTAL CAVEATS AND POTENTIAL CONFOUNDS IN AGING RESEARCH

A cursory review of age-related changes in blood flow and/or vascular density reveals marked variability in experimental results that raises broader issues within the context of gerontology. Studies that address the biological and cellular mechanisms of aging are extraordinarily complex and require attention to a number of experimental variables. However, even with rigorous attention to experimental details, issues considered generally benign in other scientific experiments have the potential to produce an immense impact on the outcome of gerontological studies. These issues include the effects of minor changes in a single variable that, over time, have the potential to impact a diverse array of experimental outcomes. For example, the presence of subclinical infections or exposure to pathogens within an animal facility clearly will produce differential effects between young and old animals. Unintended crowding of animals within cages, noise, or other non-specific stresses produce different effects in old compared to younger animals (including substantially greater losses of body weight in old compared to younger animals). Subtle changes in early husbandry experiences within a population represent a less-explored area. Within the same animal facility, the specific details of animal husbandry (room temperature, population density, handling characteristics) may be unique to a specific cohort of animals as they progress from birth to old age. Differential prenatal and early life experiences of animals have the potential to result in modifications in the development of specific tissues [1] and would likely impact the appearance of age-related pathologies and potentially unique aging trajectories and lifespan. Other issues, including specific diets, the presence of underlying pathology, and strain differences, are likely to be important sources of experimental variance. Experimental confounds related to methodology including, but not limited to, differential effects of anesthesia, fixation methods, tissue atrophy, the absence of rigorous stereological methods for counting blood vessels, and the consequences of poor categorization of cells and/or blood vessels by region, size, and function have received little attention. These and related experimental caveats undoubtedly have the potential to alter experimental outcomes and hence produce artificial, exaggerated, or attenuated effects that are labeled as “aging.” Furthermore, comparison of three age groups (young, middle-aged, and old) has been the “gold standard” for gerontological studies but these multiple age comparisons are rarely completed due to availability of animals, costs, or technical limitations associated with the experimental design. Finally, the rationale for analysis of specific ages within an animal strain has received little attention and, as a result, one might be comparing animals at the end of their lifespan (when endogenous organ systems are poorly regulated and substantial tissue pathology is present) with animals of another strain at the same chronological age but in which homeostatic mechanisms are maintained and tissue pathology is limited. Unfortunately, there are no rigorous standards between laboratories for animal husbandry in aging research and, as a result, it is not surprising (indeed it should be expected) that results on the same dependent variable within the same tissue vary between laboratories. In fact, it is sometimes remarkable the amount of agreement that does exist.

III. FUNCTIONAL CHANGES WITHIN THE CENTRAL NERVOUS SYSTEM

Impairments in tissue function are common phenomena in the aging population; however, compared to other tissues, loss of function within the central nervous system (CNS) has the potential to have more profound social and psychological consequences and can be an important factor in loss of independence. Although marked variability exists between individuals, there are numerous reports demonstrating a decline in cognitive function with age unrelated to a specific disease process. In otherwise healthy individuals, perceptual-motor performance and information processing speed, visual and auditory attention, as well as fluid intelligence are generally compromised with age [2, 3]. In addition, impairments in synaptic efficacy, neurogenesis, glucose metabolism, neurotransmitter levels, and long-term potentiation (an electrophysiological correlate of memory) are evident. Also, risk for degenerative diseases (e.g., Alzheimer’s disease, Parkinson’s disease, among others) increases and recovery from stoke damage is impaired. Although a number of cellular and subcellular correlates of this decline have been identified to date, there is no single unifying hypothesis for the decline in function of the CNS and increased risk of disease with age.

A. Cerebral Blood Flow

Whether the decline in CNS function with age is the result of a decrease in cerebral blood flow (CBF) remains a topic of considerable debate in which no consensus has emerged [4]. In part, this lack of consensus is related to some of the issues discussed previously. However, equally important is the technical difficulty in associating functional defects that occur in highly specific brain regions with an accurate measurement of flow to these same regions. Generally, the vast majority of analyses provide a “snapshot” of alterations in CBF in a large region of brain obtained under static conditions. However, the regulation of CBF is not static, and localized brain regions have the ability to regulate blood flow in response to minute alterations in metabolic requirements of the surrounding tissues. As glial and neuronal metabolism increase, blood flow increases concomitantly to support the increased metabolic requirements. Thus, local cellular metabolism and blood flow are tightly coupled in the CNS. The extremely limited data assessing the dynamic processes of changes in cerebral blood flow represent an important missing link in our analyses of age-related changes in CBF.

Despite the limitations described above, investigators using a variety of imaging methods have reported that CBF is significantly reduced in aged humans compared to young adults (see, for example, [5–7]). Similar conclusions were reached when comparing average measures of blood flow in groups of young and old subjects [8] or correlating CBF and age in individuals [9, 10]. Significantly, age-related changes in CBF appear to be regionally distinct [5, 6, 11–13] and may begin as early as middle age [10]. In addition to studies of humans, regionally specific, aging-related declines in CBF are found in both rodents and nonhuman primates [14–18]. Of course, several mechanisms regulate flow into and through each capillary bed, including the density of precapillary arterioles and capillaries [19], the structure of the vessels, and the reactivity of the arterioles (discussed in [7, 20, 21]). All or some of these mechanisms may be compromised with age.

B. Microvascular Density

The absence of an appropriate vascular network (including arterioles, arteriolar-arteriolar anastomoses, pre-capillary arterioles, and capillaries) supplying a tissue has the potential to result in inadequate blood flow either under basal conditions or conditions that require an increase in blood flow to meet metabolic demand. There are, in fact, numerous reports of age-related rarefaction or loss of arterioles in many tissues throughout the body (including cardiac and skeletal muscle [22–24]); however, only a few investigators have studied the effects of aging on the density of cerebral arterioles. Knox and Oliveira [25] reported that the number of arterioles in a strip of cortex extending from the pia to the white matter was similar in rats at 3 and 24 months of age, and Bell and Ball [26] reported an increase in arteriolar density in the subiculum of the aging human hippocampus. More recently, a substantial age-related rarefaction of the surface arterioles that supply the parenchymal vessels of the cerebral cortex was reported [24, 27]. In otherwise healthy aging rats, the density of arterioles on the cortical surface was almost 40% lower in senescent animals than in young adults (29 vs. 13 months of age, Figure 12.1). Similar decreases were evident in arteriole-arteriole anastomoses and venules (Figure 12.2), suggesting that surface vessels and possibly vasculature in deeper layers of the cortex are affected by aging. Although it is difficult to reconcile the differences in these studies due to the specific ages, species, and brain regions compared, the substantial changes observed on the cortical surface and corresponding decreases in regional blood flow provide the first evidence that rarefaction of arterioles may be an important contributing factor to decreases in blood flow with resulting impairments in cortical function.

FIGURE 12.1. (SEE COLOR INSERT FOLLOWING PAGE 204) Representative photographs of the cortical surface microvasculature in 13- and 29-month-old Brown-Norway rats, as seen through a cranial window.

FIGURE 12.1

(SEE COLOR INSERT FOLLOWING PAGE 204) Representative photographs of the cortical surface microvasculature in 13- and 29-month-old Brown-Norway rats, as seen through a cranial window. The entire parietal cranium has been removed. The cortex visible in (more...)

FIGURE 12.2. Summary of arteriolar (left), arteriole-to-arteriole anastomotic (center), and venular endpoint (right) density in male Brown-Norway rats.

FIGURE 12.2

Summary of arteriolar (left), arteriole-to-arteriole anastomotic (center), and venular endpoint (right) density in male Brown-Norway rats. Data represent mean ± SEM for 18 young, 14 middle-age, and 13 old animals. (Source: From [27]. With permission.) (more...)

The putative decrease in afferent vessels raises the question of whether there is a corresponding decrease in cerebral capillaries supplied by the afferent arterioles. As in other tissues, the length of capillary per volume of tissue arguably represents the fundamental measure of microvascular status because it determines, at the simplest level, the surface area for exchange between tissue and blood and how far a given cell is from the source of oxygen and nutrients. Surprisingly, there is as yet no striking consensus for the effects of aging on capillary density within the brain. One recent review concluded that there is little, if any, decrease in capillary density [20], whereas others report compelling evidence for an aging-related decline in capillary density [7]. How such disparate conclusions can be drawn becomes clear when one reviews the literature from the past three decades (summarized in Table 12.1, from [28]), which includes reports of aging-related decreases in capillary density, stability of capillary density from adulthood through senescence, and of increased capillary density (presumably as a result of neural atrophy). Several possibilities exist for the different conclusions. First, although significant differences exist among species, these differences alone do not account for the disparate findings reported to date. All possible age-related changes in capillary density (decrease, increase, or no change) have been reported for both humans and rats, the subjects of virtually all available studies. Second, differential responses in localized regions of the brain most likely contribute to the disparity in the literature, but regional differences alone cannot explain the varied results. In some cases, the same neural region in the same species has been examined in different laboratories and conflicting conclusions have been drawn (e.g., rat frontal cortex: [29] vs. [30–32]; rat occipital cortex: [25] vs. [30]; human frontal cortex: [33] vs. [34]). Third, capillary changes with aging may be multiphasic. At least two studies suggest that capillary density increases during late adulthood and then declines during later senescence [35, 36]. If supported, the comparison of young and old animals without the appropriate middle-aged group may potentially bias interpretation of experimental results. Finally, previous studies indicate that the magnitude of age-related changes in capillary density, where they occur, do not exceed approximately 10 to 20%.

TABLE 12.1

TABLE 12.1

Capillary Changes in the CNS with Age

Taken together, the available literature suggests there is a substantial rarefaction of surface arterioles and limited but significant changes in capillary density in some regions of the brain, including the hippocampus and cerebral cortex. However, the evidence for capillary loss is tenuous and more extensive studies are required. In part, the disparate findings for capillary density changes with aging result from methodological differences among laboratories and improved stereological methods may resolve many of these issues [48–50]. To reliably reveal the regional and temporal patterns of microvascular changes, however, it will be necessary to analyze many neural areas in a single species at multiple ages using a consistent methodology. Such studies not only are required to establish the structural bases of aging-related changes in blood flow, but also are necessary to provide the critical baseline data for studies of microvascular plasticity.

C. Microvascular Plasticity

Capillary density is highest in regions rich in synapses, somewhat lower in regions containing primarily cells bodies, and lowest in fiber tracts [7]. Even within the gray matter of the cerebral cortex, sensory and association regions have higher densities of microvessels than motor regions; within a cortical region, layers and modules with greater cytochrome oxidase activity (indicative of greater synaptic activity) have higher capillary densities [72–74]. Thus, there must be developmentally regulated mechanisms by which the elaboration of the microvasculature is matched to the local level of neuronal signaling, presumably contributing to the differential growth of more active regions of the brain [73, 75, 76].

In principle, microvascular density in each region of the brain could be genetically programmed. The developmental mechanisms must be dynamic, however, because changes in neural activity during development result in predictable changes in microvascular density. Raising animals from the time of weaning in complex environments significantly increases synaptogenesis and the growth of neuropil in the cerebral cortex [77, 78]. Greenough and colleagues also demonstrated that the associated increase in metabolic demand from this paradigm produces significant growth of new capillaries [79, 80], even after the end of the normal period of developmental angiogenesis [81].

Conversely, decreased activity reduces vascular growth. Raising animals in complete darkness is commonly used to investigate the effects of activity deprivation on cortical development. Argandona and Lafuente [82, 83] demonstrated that dark-rearing rats from the time of birth significantly decreased the elaboration of the microvascular bed in the primary visual cortex. When examined as adults, the capillary density was 22% lower in dark-reared animals than in age-matched controls. Thus, the microvasculature within the CNS is actively modified during development to maintain a match between the local level of neural activity and the level of metabolic and vascular support necessary for that activity.

For many aspects of neural development, there are critical periods during which specific aspects of neural structure or function change in response to alterations in activity [84, 85]. Critical periods may be absolute, after which no significant change is possible, or they may be relative, such that change remains possible but only in response to greater perturbations than are required to elicit plasticity during earlier development. A variety of studies indicate that, for the cerebral microvasculature, plasticity is not limited to the developmental period; rather, the microvasculature in adult animals can be altered to maintain or improve function in response to changes in activity, damage, or other perturbations. The extent to which such plasticity is maintained during aging has not been clearly defined but undoubtedly depends on the specific factors eliciting the microvascular response.

Greenough and co-workers [86] have used the enriched environment paradigm to test whether microvascular plasticity in response to increased neural activity is limited to developing animals or is maintained in adults. These investigators demonstrated that housing adult rats (2 months of age) in complex environments resulted in microvascular growth within 10 days, just as in developing rats. Additional studies revealed, however, that the extent of the effect was reduced with age. The response in middle-aged rats was less than that in young adults, and no statistically significant change in microvascular density was elicited in old rats [87]. This age-related decrement in microvascular plasticity is consistent with reports that synaptic and dendritic plasticity also are reduced in old animals [79]. Thus, it is difficult to establish whether vascular plasticity decreases with age because neuronal plasticity declines, or whether neuronal plasticity is lost because there is insufficient vascular plasticity to support the generation and maintenance of new synapses [87]. Clearly, however, this type of microvascular plasticity is maintained into adulthood but sustained only poorly, if at all, during senescence [88].

Microvascular plasticity in the adult cerebellum was also investigated to assess the influence of learning vs. increased neural activity associated with simple motor activity. Microvascular growth was seen after motor learning, which also elicited synaptogenesis and growth of neuropil, and also after simple exercise, which had no effect on synapses and neuropil [89]. Voluntary exercise increased neural activity, as evidenced by increased glucose utilization [90], suggesting that microvascular growth occurs to meet the greater metabolic demands of increased neuronal signaling, even in adult animals. Consistent with this hypothesis, recent studies find that chronic exercise in adult animals, with no motor learning, promotes microvascular growth in the cerebral cortex [91, 92]. Unfortunately, to our knowledge there exists little or no data on the effect of exercise or motor learning on vascular plasticity in aged animals.

In addition to activity-induced angiogenesis, adult microvascular plasticity is important clinically. The success of strategies for treating neurodegenerative diseases by implanting stem cells or neurons critically depends on microvascular plasticity to establish metabolic support for the foreign cells [93, 94]. Thus, several laboratories have investigated the ability of the microvasculature to invade and support new tissue or cells after implantation in the adult CNS. Following transplantation, solid tissue allografts are infiltrated and supported primarily by host blood vessels [95, 96], although some donor vessels also are maintained within the graft [97]. Host blood vessels also elaborate to support grafts of dissociated cells [98–100], in which microvascular growth is more effective than in solid grafts [101]. Given that grafts can survive in aged brains [102–105], the necessary microvascular plasticity must be maintained during senescence.

Significant microvascular plasticity also occurs in response to chronic hypoperfusion or ischemia [7, 106, 107]. The restoration of blood flow after arterial occlusion relies in part on increased blood flow through collateral vessels supplying the ischemic region [108, 109], but significant new microvascular growth also occurs [110]. This includes both sprouting from preexisting capillaries and de novo vasculogenesis involving bone marrow-derived endothelial progenitor cells [107]. Similar to the microvascular changes that accompany changes in neural activity, postischemic microvascular plasticity appears to decrease in aged animals and humans [111, 112].

Several pharmacological agents promote microvascular growth and plasticity in the adult brain. Treatment of aging animals with a calcium channel blocker from 21 to 27 months of age, for example, significantly increased capillary density in the cerebral cortex and hippocampus [31, 32]. Similarly, 4 to 6 weeks of treatment with the plant alkaloid vincamine or its derivative increased capillary density in the cortex and hippocampus of adult rats [41, 47]. The extent of microvascular response appeared to be similar in 1-year-old and 3-year-old rats. Thus, at least for the responses to these pharmacological agents, there is no significant decline in plasticity during aging.

Clarifying the mechanisms that regulate microvascular growth and function in the developing and adult brain, and establishing how those mechanisms are affected by age, is critical for understanding the nature and functional consequences of age-related changes in the brain and for assessing prospects for preventing or reversing cognitive deficits. Recent studies by Sonntag et al. [27] demonstrate that, although microvascular plasticity may be reduced, growth of precapillary arterioles can be elicited even in aged animals. The studies also suggest a potential mechanism for age-related changes in the microvasculature and related plasticity. Microvascular density on the surface of the cerebral cortex was reported to decline with age [27]. Notably, the density of surface arterioles correlated with plasma insulin-like growth factor 1 (IGF-1) levels at the time of vascular mapping. That correlation suggested that microvascular rarefaction may be the consequence of the age-related decline in circulating growth hormone and IGF-1, particularly given evidence that growth hormone and IGF-1 are important anabolic growth factors that may influence many aspects of blood vessel growth and repair [113]. Consistent with that hypothesis, twice-daily injections of growth hormone to 30-month-old animals, sufficient to increase plasma IGF-1, dramatically increased the number of cortical arterioles. Thus, growth hormone and IGF-1 appear to mediate, at least in part, age-related changes in the microvasculature and potentially cerebral blood flow [113]. Moreover, although microvascular plasticity may decline in aged animals, it can be restored if appropriate trophic conditions are present.

In addition to growth hormone and IGF-1, other trophic factors profoundly influence the microvasculature. Although their potential roles in the etiology of age-related vascular changes have not been established, both basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) significantly influence angiogenesis and microvascular plasticity. Both factors exert a mitogenic effect on human microvascular endothelial cells in culture [114, 115]. VEGF prevents cultured microvascular endothelial cells from entering replicative senescence [116]. Additionally, VEGF is upregulated in spatial and temporal coincidence with angiogenesis associated with various CNS pathologies [117–119] and is involved in exercise-induced neovascularization [120]. Expression of bFGF is upregulated endogenously in response to focal cerebral infarction in rats, and exogenous administration of bFGF improves functional recovery, potentially via induction of angiogenesis in the damaged brain [121]. These factors do not appear always to benefit the microvasculature, however, because VEGF has been implicated in the breakdown of the blood-brain barrier associated with various CNS insults [122, 123]. Thus, the roles of these factors in modulating angiogenesis are complex and require further clarification.

In addition to trophic factors such as VEGF and BDNF, endocrine growth factors influence neuronal turnover in the adult brain. Plasma-derived IGF-1 reverses the decline in hippocampal neurogenesis that is produced by hypophysectomy [124] and also ameliorates the age-related decline in neuronal turnover [125]. These findings suggest that IGF-1 is an important regulator of neurogenesis, and that the decline in neuronal turnover during senescence is the result of decreased IGF-1 levels. The effects of aging on the multiple sources of IGF-1 within the CNS remain unclear, but the decline in plasma levels of IGF-1 may be exacerbated in many regions by decreased blood flow and by microvascular rarefaction, which also would reduce local production of IGF-1 and potentially other important growth factors by endothelial and smooth muscle cells.

Understanding the relationship between microvascular plasticity and neural activity, and how aging-related changes in the microvasculature affect metabolic support for neuronal signaling, is essential for clarifying the basis of cognitive changes during senescence. Accumulating evidence suggests that age-related changes in the microvasculature also may influence other critical aspects of neural function and plasticity. As noted previously, new neurons are continually produced in some regions of the adult brain [126–128] (see also Chapter 6), and the microvasculature is critically involved in regulating adult neurogenesis, both as a local source of factors that create an appropriate milieu for neurogenesis and as the source of blood-borne factors that influence proliferation. The production of new granule neurons in the subgranular zone of the adult dentate gyrus occurs within “neuroangiogenic foci” where neuronal, glial, and endothelial precursors divide in tight clusters [129, 130]. Proliferative precursors in other regions of the hippocampus are not found within such a vascular niche and do not give rise to neurons, only glia. Thus, the association between endothelial and neuronal proliferation in the subgranular zone suggests that either signals originating from somatic tissues or from the CNS act simultaneously to stimulate neurogenesis and angiogenesis, or that the initiating signal activates proliferation of one cell type, which then stimulates proliferation of the other. A recent demonstration that intracerebroventricular infusion of VEGF into the adult brain increases the genesis of both endothelial cells and granule neurons is consistent with a mechanistic link between angiogenesis and neurogenesis [131]. Also supporting this hypothesis is evidence that the reduction in neurogenesis that follows whole brain irradiation is due, in part, to alterations in the microenvironment, including disruption of microvascular angiogenesis [132]. More direct evidence that endothelial-produced factors regulate neurogenesis comes from the demonstration that culturing precursor cells from the adult rodent forebrain subependymal zone (SZ) on monolayers of endothelial cells, rather than on astrocytes or fibroblasts, increases neurogenesis and neuronal survival [133]. Thus, much remains to be determined concerning the complex interactions between vasculature and neurons.

D. Microvascular Ultrastructure

Alterations in microvessel ultrastructure potentially contribute to alterations in both blood flow and the transport of materials across the capillary wall, even where capillary density is unchanged. The effects of aging on arteriolar and capillary ultrastructure have been recently reviewed [7, 20].

In arterioles, aging appears to decrease the distensible components of the vessel wall (smooth muscle and elastin) and increase less distensible components (collagen and basement membrane; see [51]). Along with thickening of the endothelial basement membrane, cerebral arterioles in aged animals often contain flocculent material and intracellular inclusions that are not evident in the vessels of young animals [52, 53]. These alterations in arteriolar structure presumably contribute to age-related changes in arteriolar reactivity (see below).

Age-related alterations have been described in capillary endothelial cells, their basement membrane, in pericytes, and in the astrocytic endfeet that are opposed to the abluminal vascular surface (reviewed in [7]; see also [54]). The increase in thickness of the basement membrane and the abnormal inclusions reported for aging arterioles, including enlarged perivascular space, also are evident in capillaries [37, 38, 55–61]. The complete source and mechanisms of basement membrane changes remain to be established [7], but the flocculent deposits observed in aging capillaries have been attributed to the degeneration of pericytes [62]. The various age-related ultrastructural changes in the capillary wall must be regulated by several mechanisms, because chronic treatment with calcium channel blockers decreases the deposition of extracellular collagenous fibers but has no effect on the degeneration of pericytes [58, 59]. The functional impact of these age-related alterations in the capillary wall are numerous, and are likely to include both increased leakage of materials normally excluded by the blood brain barrier and reduced transport of substances (e.g., glucose, amino acids, growth factors) that are actively transported into the brain parenchyma. Recent studies suggest that the age-related increase in leakage may be less than previously suggested [63], but that the decrease in carrier function appears to be pronounced [7].

Reports of age-related changes in the shape of arterioles and capillaries were reported in the early 20th century [64]. Although the extent of such abnormalities during normal aging is still debated [21], there are sufficient descriptions of microvessel looping, tortuosity, and twisting to conclude that such changes occur in many neural regions [20, 52, 65–69]. Whether such alterations reflect primary changes in blood vessels or secondary effects of atrophy of surrounding neural tissue is not clear, but regardless of the specific mechanism, one would expect modification of vessel shape to produce profound hemodynamic and rheological changes within the microvascular bed [52, 68–71], contributing to decreased blood flow and reduced delivery of oxygen and nutrients to the brain parenchyma.

E. Summary

In many regions of the aging brain, metabolic support for neuronal signaling may be compromised by decreased blood flow. Rarefaction of arterioles and changes in vessel shape and structure most likely contribute to reduced flow although the possibility of capillary rarefaction and the regulation of capillary density with age remains an area for additional research. The metabolic impact of reduced blood flow may be exacerbated by altered transport across the capillary wall. In addition to influencing blood vessel structure and function, aging reduces microvascular plasticity such that capillaries respond less to increases in neural activity although responses to other factors that promote angiogenesis may be maintained. The age-related loss of plasticity certainly influences neural plasticity as well, because neuronal turnover in the adult brain is linked mechanistically to capillaries and their growth. Trophic factors produced by endothelial cells are additional important regulators of ongoing neurogenesis within the adult hippocampus, and impairments in secretion of these factors may have independent actions on the aging brain. Thus, aging-related changes in microvascular structure and plasticity potentially contribute in multiple ways to the decline in cognitive function that accompanies brain aging.

IV. VASCULAR REACTIVITY

A. Age-Related Changes in Vascular Reactivity

Although decreases in vascular density and alterations in vessel ultrastructure have the ability to contribute to decreased blood flow and tissue dysfunction with age, alterations in vascular tone (basal vessel diameter) and vascular reactivity (dynamic changes in vessel diameter) are equally important because matching blood flow to tissue metabolic demand is critical for normal cellular function. Despite recent advances in the field, there are conflicting reports of age-related alterations in cerebrovascular tone and reactivity in the literature. For example, Thorin-Trescases [134] observed no effect of age on arterial tone in isolated human pial vessels with diameters ranging between 300–1200 microns, whereas Geary and Buchholz [135] reported increased middle cerebral artery tone in aged Fisher-344 rats. This inconsistency is potentially the result of a disparity in the size and location of the vessels examined, as well as species-based differences in vascular responses. However, recent studies in our laboratory indicate that there are age-related changes in vascular tone and reactivity, and that these alterations are secondary to changes in the balance between endothelium-derived relaxing and contracting factors released from either the micro- and/or macro-circulation (D.M. Eckman et al., unpublished data).

B. Role of the Endothelium in Aging

Ultimately, blood flow through a vessel depends on the close interactions of several cell types that compose the vessel wall. Endothelial cells and smooth muscle cells form the basis of this interaction; the complex interactions between relaxing and constricting factors derived from endothelial cells result in a dynamic regulation of vascular smooth muscle cell activity, vessel dilation or constriction, and hence regulation of blood flow to tissue. Mechanistically, endothelium-dependent relaxing factors (EDRFs) result in hyperpolarization of smooth muscle cells and dilation, whereas endothelium-derived constriction factors (EDCFs) result in smooth muscle depolarization and vessel constriction. The roles of each of these factors are discussed below. Despite the recognized importance of these factors in the regulation of cerebral blood flow, there is generally little information available on age-related changes in vessel tone and reactivity in the cerebral circulation. Therefore, data from other vascular beds are presented such that they might provide some insight into potential age-related changes in the cerebrovascular system.

FIGURE 12.3. (SEE COLOR INSERT FOLLOWING PAGE 204) The degree of vascular constriction (vascular tone) regulates blood flow and depends on a close communication between endothelial cells (ENDO) and smooth muscle cells (SMC).

FIGURE 12.3

(SEE COLOR INSERT FOLLOWING PAGE 204) The degree of vascular constriction (vascular tone) regulates blood flow and depends on a close communication between endothelial cells (ENDO) and smooth muscle cells (SMC). Endothelium-dependent relaxing factors (more...)

1. Endothelium-Derived Relaxing Factors (EDRFs)

a. Nitric Oxide (NO)

The contribution of nitric oxide (NO) to the modulation of vascular tone has been the focus of multiple human and animal studies. The primary source of NO in the cerebral circulation is endothelial nitric oxide synthase (eNOS). As the name suggests, eNOS is located in the endothelial cells that line the lumen of the blood vessel. NO diffuses to vascular smooth muscle cells where it increases cGMP formation through the activation of cyclic guanylate cyclase (cGC). Activation of this pathway results in the dilation of vascular smooth muscle via multiple mechanisms. While the role of NO signaling in healthy aging-associated vascular dysfunction is not well understood, there are both human and animal studies that provide compelling data suggesting that altered vascular function associated with advancing age may be attributed, at least in part, to perturbations in NO signaling [136–144]. For example, in carotid arteries from aging mice [143], as well as forearm vessels of healthy elderly humans [142], vessel dilation following acetylcholine (ACh) administration (which stimulates endothelial NO production) is significantly reduced, suggesting a blunted production of NO occurs in endothelial cells with age. However, both of these studies also showed reduced vessel dilation in response to sodium nitroprusside (SNP), which directly donates NO to smooth muscle cells. Taken together, these data suggest both endothelial-dependent NO production and endothelial-independent NO sensitivity are altered with aging. In contrast, at least one study reported no age-related differences in coronary artery responses to ACh or nitroprusside have been observed in 24-month-old male F344 rats [145]. These inconsistent findings may reflect methodological differences but more importantly suggest that the mechanisms of age-related vascular dysfunction may be unique to each vascular bed and species.

The mechanisms underlying the disrupted NO signaling with aging identified thus far appear to be complex. In the systemic circulation, both an increase and a decrease in nitric oxide synthase (NOS) activity have been reported [146, 147], as well as an age-associated decrease in agonist-induced vascular cGMP levels [141, 148–150]. In middle cerebral arteries from Fisher-344 rats, Geary and Buchholz [135] demonstrated an increase in arterial tone with advancing age, a finding that appears to be, at least in part, secondary to the dysfunction of eNOS-sensitive mechanisms. Others report declines in the levels of the β subunit of soluble guanylate cyclase (sGC) and reduced sGC activity [141], reduced protein kinase G-1 (PKG-1) activation [151], and decreased eNOS mRNA expression [144, 147, 152] and phosphorylation [153]. Finally, either unchanged [145, 154] or increased eNOS protein expression has been reported in aged vasculature [138, 154–159].

b. Endothelium-Derived Hyperpolarizing Factors (EDHFs)

It is well accepted that endothelium-derived hyperpolarizing factors (EDHFs) are important regulators of vascular tone in resistance-size arteries. However, the role of EDHFs in modulating vascular tone in the aging systemic circulation, especially in cerebral circulation, has received little attention. Interestingly, aging appears to significantly impair EDHF-mediated relaxations in isolated human gastroepiploic arteries, distal microvessels [160], and gracilis arterial segments [161]. In contrast, the magnitude of EDHF-mediated relaxation of renal arteries from WKY rats appears unaffected by increasing age [162].

2. Endothelium-Derived Contracting Factors (EDCFs)

a. Endothelin

There are limited data regarding the role of the potent vasoconstrictor, endothelin, in the modulation of vascular tone with age. Barton and colleagues [152] reported a rise in plasma endothelin-1 (ET-1) levels with increasing age in old female Ro-Ro Wistar rats (32 to 33 months). Furthermore, they have shown attenuated ET-1-induced constriction in the aorta but not the femoral artery of old female rats [152]. In contrast, the contractile response to ET-1 has been shown to increase in coronary arteries from aged Wistar-Kyoto [163] and Fisher-344 rats [145], as well as in basilar arteries from aged female rats [164]. Selective inhibition of endothelin-A receptors in young animals abolishes ET-1-induced coronary artery constriction, whereas inhibition of these receptors in aged animals has no effect on ET-1-induced constriction [145]. Thus, the role of endothelin in the modulation of vascular tone and reactivity in the aging vasculature appears complex and requires further investigation.

b. Prostanoids

The role of prostanoids, which include prostaglandins, prostacyclin, and thromboxane, in vascular regulation is well known. These molecules are created from arachidonic acid by cyclooxygenase (COX-1 and COX-2) and prostaglandin H synthase (PGHS-1 and PGHS-2) in most mammalian cells. In vasculature, prostanoids, especially thromboxane, stimulate vasoconstriction. Recent data suggest that aging results in a significant increase of thromboxane A2 and the prostaglandins PGE2, PGF2alpha, and PGI2 [165, 166]. Other studies have shown that the blunted vasodilatory response of aged vessels to administration of ACh or SNP, while partially attributable to dysregulation of NO, could be partially or completely reversed by inhibition of COX [138, 167] or PGHS2 [168]. Additionally, Davidge and colleagues [167] found that COX inhibition reversed an age-related hypersensitivity to administration of the vasoconstrictor phenylephrine [167]. Furthermore, age-related impairments in vasodilatory responses can be ameliorated by thromboxane A2/PGH2 receptor blockade [138, 167, 168]. Finally, age-associated endothelial dysfunction appears to occur as early as 12 months of age via inhibition of the synthesis of COX-2-derived constrictors as well as superoxide anions [169], suggesting an important role for prostanoids in the vascular dysfunction seen with aging.

c. Reactive Oxygen Species (ROS)

There are extensive data suggesting that oxidative stress plays an important role in the mechanisms of aging in multiple tissues [170] (see also Chapter 15). This concept is supported by data revealing a direct correlation between the activity of superoxide dismutase (SOD), an endogenous antioxidant, and lifespan in several species [171]. Although it is well recognized that changes in the antioxidant profile occur with advancing age, relatively little is known regarding the role of oxidative stress in aging-associated vascular dysfunction. In cultured aortic vascular smooth muscle cells from 16-month-old mice, reduced SOD activity has been shown to result in increased levels of reactive oxygen species (ROS) as well as increased lipid peroxidation and damage to mitochondrial DNA[172]. In aging rats and mice, increased ROS production has been linked to decreased NO bioavailability [143, 173], with concomitant quenching of NO by the formation of peroxynitrite followed by nitration and inhibition of mitochondrial MnSOD [174]. These alterations have the potential to interfere with endothelial NO signaling, resulting in increased vasoconstrictive tone in aged vessels. Indeed, coronary arterioles from aging rats show significantly diminished flow-induced, NO-mediated dilation as a result of increased O2 anion and peroxynitrite production [144]. In contrast to the above data, at least one study reported that, despite increasing oxidative stress in both male and female Fisher-344 × Brown Norway rats with advancing age, vascular function appears to be preserved in mesenteric arteries [175]. Thus, specific vascular beds may be sensitive to increased oxidative stress associated with age, whereas others may be relatively insensitive to such effects.

C. Summary

Perturbations in multiple signaling pathways (NO, EDHF, ROS, prostanoids) have been described in different vascular beds in the healthy aging animal. The majority of the research to date suggests that endothelium-dependent responses are attenuated, primarily due to decreased NO production and/or impaired downstream signaling in the NO pathway. The apparent decrease in endothelium-dependent vasodilators coincides with an increase in endothelium-dependent vasoconstrictors in many vascular beds. Additionally, there is an evolving literature suggesting that both ROS and prostanoids may be responsible for elevated vasoconstrictor activity. As most of the aforementioned information is derived from peripheral vascular studies, the mechanism(s) underlying cerebral vascular dysfunction in the aging animal remain unknown. It is well accepted that the cerebral circulation is highly autoregulated. Small changes in arterial tone result in rapid adjustment of regional cerebral blood flow to meet neuronal and metabolic demands. Although it can be argued that the effects of aging on cerebral circulation are predictable based on other vascular beds, the diversity of changes observed in other vascular beds with age argue against this position [176]. In addition, the basic control mechanisms in the cerebral circulation are unique compared to other vascular beds and include, but are not limited to, features such as the blood-brain barrier, perivascular innervation, intracellular communication between neurons, perivascular glial cells, and smooth muscle cells, a high tissue metabolic rate, lack of anoxic tolerance, and the presence of collateral arteries in some species. Therefore, extrapolation of findings from other vascular beds to the cerebral circulation is difficult, and further studies of the altered regulation of the cerebrovasculature in aged animals are necessary.

V. CONCLUSION

Cerebrovascular aging can be viewed from several perspectives, including alterations in vascular density (the number of capillaries and arterioles), vascular plasticity (the dynamic regulation of vessel density or structure), and vascular reactivity (the adjustment of vessels to acute metabolic changes that occur in tissues). There is evidence that in otherwise healthy humans and animals, age-related changes occur in each of these variables. Data on vascular changes in the brain with aging are limited by the absence of highly controlled studies, as well as by the complexities common to gerontological investigations. Nevertheless, there are substantial data that the density of some cerebral vessels, especially precapillary arterioles, decreases with age. However, the analysis of capillary density can be more challenging, and the introduction of stereological analyses may aid in the development of more precise analyses and resolve some of the current controversies. Certainly the growth of new vessels appears to be compromised with age, which has important implications for management of disease processes including stroke. Finally, matching acute metabolic changes to alterations in blood flow is critical for normal tissue function. Unfortunately, the majority of data on microvascular reactivity has been gathered from peripheral vascular beds. Whether changes in the cerebrovasculature are similar to those in the periphery remain to be established. However, each vascular bed appears to have unique regulatory properties and therefore additional direct studies will be required. The underlying basic question to be addressed is whether age-related alterations in blood flow or transport of nutrients from blood to brain limit tissue function in highly localized areas of the brain and directly or indirectly lead to impaired function. Obviously this is a complex question that will require non-invasive imaging techniques that are still in development. Once these studies are complete, the detailed studies of vascular density and vessel reactivity that are ongoing can be integrated to determine whether pharmacological interventions can be designed to improve function.

ACKNOWLEDGMENTS

This work was supported by National Institutes of Health Grants P01 AG11370 (WES and DRR) and R01 AG19886 (DRR).

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