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INTRODUCTION: Age-related blood-brain barrier (BBB) disruption, cerebromicrovascular senescence, and microvascular rarefaction substantially contribute to the pathogenesis of vascular cognitive impairment (VCI) and Alzheimer's disease (AD). Previous studies established a causal link between age-related decline in circulating levels of insulin-like growth factor-1 (IGF-1), cerebromicrovascular dysfunction, and cognitive decline. The aim of our study was to determine the effect of IGF-1 signaling on senescence, BBB permeability, and vascular density in middle-age and old brains. METHODS: Accelerated endothelial senescence was assessed in senescence reporter mice (VE-Cadherin-CreERT2 /Igf1rfl/fl × p16-3MR) using flow cytometry. To determine the functional consequences of impaired IGF-1 input to cerebromicrovascular endothelial cells, BBB integrity and capillary density were studied in mice with endothelium-specific knockout of IGF1R (VE-Cadherin-CreERT2 /Igf1rfl/fl ) using intravital two-photon microscopy. RESULTS: In VE-Cadherin-CreERT2 /Igf1rfl/fl mice: (1) there was an increased presence of senescent endothelial cells; (2) cumulative permeability of the microvessels to fluorescent tracers of different molecular weights (0.3-40 kDa) is significantly increased, as compared to that of control mice, whereas decline in cortical capillary density does not reach statistical significance. CONCLUSIONS: These findings support the notion that IGF-1 signaling plays a crucial role in preserving a youthful cerebromicrovascular endothelial phenotype and maintaining the integrity of the BBB.
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Barrera Hematoencefálica , Factor I del Crecimiento Similar a la Insulina , Animales , Ratones , Barrera Hematoencefálica/patología , Factor I del Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/metabolismo , Péptidos Similares a la Insulina , Células Endoteliales/metabolismo , Envejecimiento/patología , Encéfalo/irrigación sanguínea , Fenotipo , Endotelio , Senescencia CelularRESUMEN
Inflammation can impair intestinal barrier, while increased epithelial permeability can lead to inflammation. In this study, we found that the expression of Tspan8, a tetraspanin expressed specifically in epithelial cells, is downregulated in mouse model of ulcerative disease (UC) but correlated with those of cell-cell junction components, such as claudins and E-cadherin, suggesting that Tspan8 supports intestinal epithelial barrier. Tspan8 removal increases intestinal epithelial permeability and upregulates IFN-γ-Stat1 signaling. We also demonstrated that Tspan8 coalesces with lipid rafts and facilitates IFNγ-R1 localization at or near lipid rafts. As IFN-γ induces its receptor undergoing clathrin- or lipid raft-dependent endocytosis and IFN-γR endocytosis plays an important role in Jak-Stat1 signaling, our analysis on IFN-γR endocytosis revealed that Tspan8 silencing impairs lipid raft-mediated but promotes clathrin-mediated endocytosis of IFN-γR1, leading to increased Stat1 signaling. These changes in IFN-γR1 endocytosis upon Tspan8 silencing correlates with fewer lipid raft component GM1 at the cell surface and more clathrin heavy chain in the cells. Our findings indicate that Tspan8 determines the IFN-γR1 endocytosis route, to restrain Stat1 signaling, stabilize intestine epithelium, and subsequently prevent intestine from inflammation. Our finding also implies that Tspan8 is needed for proper endocytosis through lipid rafts.
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Mucosa Intestinal , Receptores de Interferón , Tetraspaninas , Animales , Ratones , Clatrina/metabolismo , Endocitosis/fisiología , Inflamación/metabolismo , Interferones/metabolismo , Mucosa Intestinal/metabolismo , Receptores de Interferón/metabolismo , Tetraspaninas/genética , Tetraspaninas/metabolismoRESUMEN
INTRODUCTION: Mild cognitive impairment (MCI) is a prodromal stage of dementia. Understanding the mechanistic changes from healthy aging to MCI is critical for comprehending disease progression and enabling preventative intervention. METHODS: Patients with MCI and age-matched controls (CN) were administered cognitive tasks during functional near-infrared spectroscopy (fNIRS) recording, and changes in plasma levels of extracellular vesicles (EVs) were assessed using small-particle flow cytometry. RESULTS: Neurovascular coupling (NVC) and functional connectivity (FC) were decreased in MCI compared to CN, prominently in the left-dorsolateral prefrontal cortex (LDLPFC). We observed an increased ratio of cerebrovascular endothelial EVs (CEEVs) to total endothelial EVs in patients with MCI compared to CN, correlating with structural MRI small vessel ischemic damage in MCI. LDLPFC NVC, CEEV ratio, and LDLPFC FC had the highest feature importance in the random Forest group classification. DISCUSSION: NVC, CEEVs, and FC predict MCI diagnosis, indicating their potential as markers for MCI cerebrovascular pathology. HIGHLIGHTS: Neurovascular coupling (NVC) is impaired in mild cognitive impairment (MCI). Functional connectivity (FC) compensation mechanism is lost in MCI. Cerebrovascular endothelial extracellular vesicles (CEEVs) are increased in MCI. CEEV load strongly associates with cerebral small vessel ischemic lesions in MCI. NVC, CEEVs, and FC predict MCI diagnosis over demographic and comorbidity factors.
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Biomarcadores , Disfunción Cognitiva , Vesículas Extracelulares , Acoplamiento Neurovascular , Humanos , Disfunción Cognitiva/fisiopatología , Vesículas Extracelulares/metabolismo , Femenino , Masculino , Anciano , Biomarcadores/sangre , Acoplamiento Neurovascular/fisiología , Imagen por Resonancia Magnética , Espectroscopía Infrarroja Corta , Persona de Mediana EdadRESUMEN
PURPOSE: Acute decompensated heart failure (ADHF) is associated with inflammation, oxidative stress, and excess sympathetic drive. It is unknown whether neuromodulation would improve inflammation and oxidative stress in acute heart failure. We, therefore, performed this proof-of-concept study to evaluate the effects of neuromodulation using noninvasive low-level tragus stimulation on inflammation and oxidative stress in ADHF. METHODS: Nineteen patients with ejection fraction < 40% were randomized to neuromodulation 4 h twice daily (6-10 a.m. and 6-10 p.m.) (n = 8) or sham stimulation (n = 11) during hospital admission. All patients received standard-of-care treatment. Blood samples were collected at admission and discharge. Serum cytokines were assayed using standard immunosorbent techniques. Reactive oxygen species inducibility from cultured coronary endothelial cells exposed to patient sera was determined using a dihydrodichlorofluorescein probe test (expressed as fluorescein units). RESULTS: Compared to sham stimulation, neuromodulation was associated with a significant reduction of circulating serum interleukin-6 levels (-78% vs. -9%; p = 0.012). Similarly, neuromodulation led to a reduction of endothelial cell oxidative stress in the neuromodulation group (1363 units to 978 units, p = 0.003) compared to sham stimulation (1146 units to 1083 units, p = 0.094). No significant differences in heart rate, blood pressure, or renal function were noted between the two groups. CONCLUSION: In this proof-of-concept pilot study, in acute decompensated heart failure, neuromodulation was feasible and safe and was associated with a reduction in systemic inflammation and attenuation of coronary endothelial cellular oxidative stress. CLINICAL TRIAL REGISTRATION: NCT02898181.
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Células Endoteliales , Insuficiencia Cardíaca , Humanos , Proyectos Piloto , Insuficiencia Cardíaca/terapia , Inflamación/terapia , Estrés OxidativoRESUMEN
Peripheral artery disease (PAD) is a vascular pathology with high prevalence among the aging population. PAD is associated with decreased cognitive performance, but the underlying mechanisms remain obscure. Normal brain function critically depends on an adequate adjustment of cerebral blood supply to match the needs of active brain regions via neurovascular coupling (NVC). NVC responses depend on healthy microvascular endothelial function. PAD is associated with significant endothelial dysfunction in peripheral arteries, but its effect on NVC responses has not been investigated. This study was designed to test the hypothesis that NVC and peripheral microvascular endothelial function are impaired in PAD. We enrolled 11 symptomatic patients with PAD and 11 age- and sex-matched controls. Participants were evaluated for cognitive performance using the Cambridge Neuropsychological Test Automated Battery and functional near-infrared spectroscopy to assess NVC responses during the cognitive n-back task. Peripheral microvascular endothelial function was evaluated using laser speckle contrast imaging. We found that cognitive performance was compromised in patients with PAD, evidenced by reduced visual memory, short-term memory, and sustained attention. We found that NVC responses and peripheral microvascular endothelial function were significantly impaired in patients with PAD. A positive correlation was observed between microvascular endothelial function, NVC responses, and cognitive performance in the study participants. Our findings support the concept that microvascular endothelial dysfunction and neurovascular uncoupling contribute to the genesis of cognitive impairment in older PAD patients with claudication. Longitudinal studies are warranted to test whether the targeted improvement of NVC responses can prevent or delay the onset of PAD-associated cognitive decline.NEW & NOTEWORTHY Peripheral artery disease (PAD) was associated with significantly decreased cognitive performance, impaired neurovascular coupling (NVC) responses in the prefrontal cortex (PFC), left and right dorsolateral prefrontal cortices (LDLPFC and RDLPFC), and impaired peripheral microvascular endothelial function. A positive correlation between microvascular endothelial function, NVC responses, and cognitive performance may suggest that PAD-related cognitive decrement is mechanistically linked, at least in part, to generalized microvascular endothelial dysfunction and subsequent impairment of NVC responses.
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Disfunción Cognitiva , Acoplamiento Neurovascular , Enfermedad Arterial Periférica , Anciano , Envejecimiento/fisiología , Arteriolas , Circulación Cerebrovascular/fisiología , Humanos , Acoplamiento Neurovascular/fisiologíaRESUMEN
Over two-thirds of individuals aged 65 and older are obese or overweight in the United States. Epidemiological data show an association between the degree of adiposity and cognitive dysfunction in the elderly. In this review, the pathophysiological roles of microvascular mechanisms, including impaired endothelial function and neurovascular coupling responses, microvascular rarefaction, and blood-brain barrier disruption in the genesis of cognitive impairment in geriatric obesity are considered. The potential contribution of adipose-derived factors and fundamental cellular and molecular mechanisms of senescence to exacerbated obesity-induced cerebromicrovascular impairment and cognitive decline in aging are discussed.
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Barrera Hematoencefálica/fisiopatología , Cognición , Disfunción Cognitiva/fisiopatología , Endotelio Vascular/fisiopatología , Microvasos/fisiopatología , Acoplamiento Neurovascular , Obesidad/fisiopatología , Factores de Edad , Anciano , Animales , Barrera Hematoencefálica/metabolismo , Envejecimiento Cognitivo , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/prevención & control , Disfunción Cognitiva/psicología , Endotelio Vascular/metabolismo , Femenino , Humanos , Masculino , Microcirculación , Microvasos/metabolismo , Obesidad/epidemiología , Obesidad/psicología , Obesidad/terapia , Medición de Riesgo , Factores de RiesgoRESUMEN
Age-related blood-brain barrier (BBB) disruption and cerebromicrovascular rarefaction contribute importantly to the pathogenesis of both vascular cognitive impairment and dementia (VCID) and Alzheimer's disease (AD). Recent advances in geroscience research enable development of novel interventions to reverse age-related alterations of the cerebral microcirculation for prevention of VCID and AD. To facilitate this research, there is an urgent need for sensitive and easy-to-adapt imaging methods that enable longitudinal assessment of changes in BBB permeability and brain capillarization in aged mice and that could be used in vivo to evaluate treatment efficiency. To enable longitudinal assessment of changes in BBB permeability in aged mice equipped with a chronic cranial window, we adapted and optimized two different intravital two-photon imaging approaches. By assessing relative fluorescence changes over the baseline within a volume of brain tissue, after qualitative image subtraction of the brain microvasculature, we confirmed that, in 24-mo-old C57BL/6J mice, cumulative permeability of the microvessels to fluorescent tracers of different molecular masses (0.3 to 40 kDa) is significantly increased compared with that of 5-mo-old mice. Real-time recording of vessel cross-sections showed that apparent solute permeability of single microvessels is significantly increased in aged mice vs. young mice. Cortical capillary density, assessed both by intravital two-photon microscopy and optical coherence tomography was also decreased in aged mice vs. young mice. The presented methods have been optimized for longitudinal (over the period of 36 wk) in vivo assessment of cerebromicrovascular health in preclinical geroscience research.NEW & NOTEWORTHY Methods are presented for longitudinal detection of age-related increase in blood-brain barrier permeability and microvascular rarefaction in the mouse cerebral cortex by intravital two-photon microscopy and optical coherence tomography.
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Envejecimiento/patología , Barrera Hematoencefálica/diagnóstico por imagen , Permeabilidad Capilar , Corteza Cerebral/irrigación sanguínea , Microscopía Intravital , Microscopía de Fluorescencia por Excitación Multifotónica , Rarefacción Microvascular , Microvasos/diagnóstico por imagen , Tomografía de Coherencia Óptica , Factores de Edad , Envejecimiento/metabolismo , Animales , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/patología , Masculino , Ratones Endogámicos C57BL , Densidad Microvascular , Microvasos/metabolismo , Microvasos/patología , Factores de TiempoRESUMEN
Aging of the vasculature plays a central role in morbidity and mortality of older people. To develop novel treatments for amelioration of unsuccessful vascular aging and prevention of age-related vascular pathologies, it is essential to understand the cellular and functional changes that occur in the vasculature during aging. In this review, the pathophysiological roles of fundamental cellular and molecular mechanisms of aging, including oxidative stress, mitochondrial dysfunction, impaired resistance to molecular stressors, chronic low-grade inflammation, genomic instability, cellular senescence, epigenetic alterations, loss of protein homeostasis, deregulated nutrient sensing, and stem cell dysfunction in the vascular system are considered in terms of their contribution to the pathogenesis of both microvascular and macrovascular diseases associated with old age. The importance of progeronic and antigeronic circulating factors in relation to development of vascular aging phenotypes are discussed. Finally, future directions and opportunities to develop novel interventions to prevent/delay age-related vascular pathologies by targeting fundamental cellular and molecular aging processes are presented.
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Envejecimiento/metabolismo , Arterias/metabolismo , Enfermedades Cardiovasculares/metabolismo , Senescencia Celular , Mediadores de Inflamación/metabolismo , Estrés Oxidativo , Factores de Edad , Envejecimiento/genética , Envejecimiento/patología , Animales , Arterias/patología , Arterias/fisiopatología , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/patología , Enfermedades Cardiovasculares/fisiopatología , Metabolismo Energético , Epigénesis Genética , Inestabilidad Genómica , Humanos , Mitocondrias/genética , Mitocondrias/metabolismo , Mitocondrias/patología , Fenotipo , Proteostasis , Transducción de SeñalRESUMEN
Age-related alterations in endothelium and the resulting vascular dysfunction critically contribute to a range of pathological conditions associated with old age. To develop therapies rationally that improve vascular health and thereby increase health span and life span in older adults, it will be essential to understand the cellular and molecular mechanisms contributing to vascular aging. Preclinical studies in model organisms demonstrate that NAD+ availability decreases with age in multiple tissues and that supplemental NAD+ precursors can ameliorate many age-related cellular impairments. Here, we provide a comprehensive overview of NAD+-dependent pathways [including the NAD+-using silent information regulator-2-like enzymes and poly(ADP-ribose) polymerase enzymes] and the potential consequences of endothelial NAD+ deficiency in vascular aging. The multifaceted vasoprotective effects of treatments that reverse the age-related decline in cellular NAD+ levels, as well as their potential limitations, are discussed. The preventive and therapeutic potential of NAD+ intermediates as effective, clinically relevant interventions in older adults at risk for ischemic heart disease, vascular cognitive impairment, and other common geriatric conditions and diseases that involve vascular pathologies (e.g., sarcopenia, frailty) are critically discussed. We propose that NAD+ precursors [e.g., nicotinamide (Nam) riboside, Nam mononucleotide, niacin] should be considered as critical components of combination therapies to slow the vascular aging process and increase cardiovascular health span.
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Envejecimiento/metabolismo , Endotelio Vascular/metabolismo , NAD/deficiencia , Enfermedades Vasculares/metabolismo , Factores de Edad , Envejecimiento/patología , Animales , Senescencia Celular , Endotelio Vascular/patología , Endotelio Vascular/fisiopatología , Metabolismo Energético , Humanos , Estrés Oxidativo , Transducción de Señal , Enfermedades Vasculares/patología , Enfermedades Vasculares/fisiopatologíaRESUMEN
There has been an increasing appreciation of the role of vascular contributions to cognitive impairment and dementia (VCID) associated with old age. Strong preclinical and translational evidence links age-related dysfunction and structural alterations of the cerebral arteries, arterioles, and capillaries to the pathogenesis of many types of dementia in the elderly, including Alzheimer's disease. The low-pressure, low-velocity, and large-volume venous circulation of the brain also plays critical roles in the maintenance of homeostasis in the central nervous system. Despite its physiological importance, the role of age-related alterations of the brain venous circulation in the pathogenesis of vascular cognitive impairment and dementia is much less understood. This overview discusses the role of cerebral veins in the pathogenesis of VCID. Pathophysiological consequences of age-related dysregulation of the cerebral venous circulation are explored, including blood-brain barrier disruption, neuroinflammation, exacerbation of neurodegeneration, development of cerebral microhemorrhages of venous origin, altered production of cerebrospinal fluid, impaired function of the glymphatics system, dysregulation of cerebral blood flow, and ischemic neuronal dysfunction and damage. Understanding the age-related functional and phenotypic alterations of the cerebral venous circulation is critical for developing new preventive, diagnostic, and therapeutic approaches to preserve brain health in older individuals.
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Venas Cerebrales/fisiopatología , Circulación Cerebrovascular , Cognición , Envejecimiento Cognitivo/psicología , Disfunción Cognitiva/fisiopatología , Demencia Vascular/fisiopatología , Factores de Edad , Animales , Disfunción Cognitiva/líquido cefalorraquídeo , Disfunción Cognitiva/etiología , Disfunción Cognitiva/psicología , Demencia Vascular/líquido cefalorraquídeo , Demencia Vascular/etiología , Demencia Vascular/psicología , Humanos , Factores de RiesgoRESUMEN
Aging is the major risk factor for cardiovascular diseases, which are the leading cause of death in the United States. Traditionally, the effort to prevent cardiovascular disease has been focused on addressing the conventional risk factors, including hypertension, hyperglycemia, hypercholesterolemia, and high circulating levels of triglycerides. However, recent preclinical studies have identified new approaches to combat cardiovascular disease. Calorie restriction has been reproducibly shown to prolong lifespan in various experimental model animals. This has led to the development of calorie restriction mimetics and other pharmacological interventions capable to delay age-related diseases. In this review, we will address the mechanistic effects of aging per se on the cardiovascular system and focus on the prolongevity benefits of various therapeutic strategies that support cardiovascular health.
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Envejecimiento/metabolismo , Enfermedades Cardiovasculares/metabolismo , Envejecimiento/efectos de los fármacos , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Restricción Calórica , Enfermedades Cardiovasculares/dietoterapia , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/prevención & control , HumanosRESUMEN
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.
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Envejecimiento , Circulación Cerebrovascular , Disfunción Cognitiva/fisiopatología , Demencia/fisiopatología , Endotelio Vascular/fisiopatología , Microcirculación , Acoplamiento Neurovascular , Homeostasis , HumanosRESUMEN
The increasing prevalence of multifocal cerebral microhemorrhages (CMHs, also known as "cerebral microbleeds") is a significant, newly recognized problem in the aging population of the Western world. CMHs are associated with rupture of small intracerebral vessels and are thought to progressively impair neuronal function, potentially contributing to cognitive decline, geriatric psychiatric syndromes, and gait disorders. Clinical studies show that aging and hypertension significantly increase prevalence of CMHs. CMHs are also now recognized by the National Institutes of Health as a major factor in Alzheimer's disease pathology. Moreover, the presence of CMHs is an independent risk factor for subsequent larger intracerebral hemorrhages. In this article, we review the epidemiology, detection, risk factors, clinical significance, and pathogenesis of CMHs. The potential age-related cellular mechanisms underlying the development of CMHs are discussed, with a focus on the structural determinants of microvascular fragility, age-related alterations in cerebrovascular adaptation to hypertension, the role of oxidative stress and matrix metalloproteinase activation, and the deleterious effects of arterial stiffening, increased pulse pressure, and impaired myogenic autoregulatory protection on the brain microvasculature. Finally, we examine potential treatments for the prevention of CMHs based on the proposed model of aging- and hypertension-dependent activation of the reactive oxygen species-matrix metalloproteinases axis, and we discuss critical questions to be addressed by future studies.
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Hemorragia Cerebral/prevención & control , Hemorragia Cerebral/fisiopatología , Circulación Cerebrovascular , Microcirculación , Microvasos/fisiopatología , Factores de Edad , Anciano , Envejecimiento , Animales , Hemorragia Cerebral/diagnóstico por imagen , Hemorragia Cerebral/epidemiología , Hemorragia Cerebral/psicología , Cognición , Trastornos del Conocimiento/epidemiología , Trastornos del Conocimiento/fisiopatología , Trastornos del Conocimiento/psicología , Matriz Extracelular/metabolismo , Femenino , Hemodinámica , Humanos , Hipertensión/epidemiología , Hipertensión/fisiopatología , Imagen por Resonancia Magnética , Masculino , Metaloproteinasas de la Matriz/metabolismo , Memoria , Trastornos de la Memoria/epidemiología , Trastornos de la Memoria/fisiopatología , Trastornos de la Memoria/psicología , Microvasos/metabolismo , Microvasos/patología , Persona de Mediana Edad , Pronóstico , Especies Reactivas de Oxígeno/metabolismo , Factores de Riesgo , Remodelación VascularRESUMEN
OBJECTIVE: The primary aim of the study was to assess whether both the amount and pace of daily walking were associated with circulating antioxidant capacity in symptomatic patients with peripheral artery disease (PAD). METHODS: Community-based walking was measured in 244 men and women who were limited by symptomatic PAD during a 1-week period in which they wore an ankle-mounted step activity monitor. Patients were further characterized by circulating antioxidant capacity with the OxiSelect (Cell Biolabs Inc, San Diego, Calif) hydroxyl radical antioxidant capacity (HORAC) activity assay. RESULTS: To assess the amount of walking, patients were grouped into low (≤2440 strides/d), middle (2441-3835 strides/d), and high (>3835 strides/d) stride tertiles. HORAC was higher in the middle (P = .03) and high (P = .01) stride tertiles than in the low tertile, but there was no difference between middle and high tertiles (P = .44). To assess the pace of walking, patients were grouped into slow (<25.0 strides/min), middle (25.0-31.6 strides/min), and fast (>31.6 strides/min) cadence tertiles. HORAC was higher in the high cadence tertile than in the low (P < .01) and middle (P < .01) tertiles, but there was no difference between low and middle tertiles (P = .48). Similar findings were obtained on group differences in HORAC after adjusting for age, sex, race, and ankle-brachial index for both the amount and pace of daily walking. CONCLUSIONS: Walking >2440 strides each day and walking at a cadence faster than 31.6 strides/min for 30 minutes each day are both associated with greater circulating antioxidant capacity in symptomatic patients with PAD. The clinical significance is that a home-based walking program may be one approach to increase endogenous antioxidant capacity.
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Antioxidantes/metabolismo , Terapia por Ejercicio/métodos , Estrés Oxidativo , Enfermedad Arterial Periférica/terapia , Caminata , Actigrafía/instrumentación , Anciano , Índice Tobillo Braquial , Apoptosis , Biomarcadores/sangre , Proteína C-Reactiva/metabolismo , Células Cultivadas , Servicios de Salud Comunitaria , Células Endoteliales/metabolismo , Células Endoteliales/patología , Prueba de Esfuerzo , Femenino , Monitores de Ejercicio , Humanos , Radical Hidroxilo/sangre , Mediadores de Inflamación/sangre , Masculino , Persona de Mediana Edad , Oklahoma , Enfermedad Arterial Periférica/sangre , Enfermedad Arterial Periférica/complicaciones , Enfermedad Arterial Periférica/fisiopatología , Estudios Prospectivos , Factores de Tiempo , Transfección , Resultado del TratamientoRESUMEN
In humans, the developmental origins of interneurons in the third trimester of pregnancy and the timing of completion of interneuron neurogenesis have remained unknown. Here, we show that the total and cycling Nkx2.1(+)and Dlx2(+)interneuron progenitors as well as Sox2(+)precursor cells were higher in density in the medial ganglionic eminence (MGE) compared with the lateral ganglionic eminence and cortical ventricular/subventricular zone (VZ/SVZ) of 16-35 gw subjects. The proliferation of these progenitors reduced as a function of gestational age, almost terminating by 35 gw. Proliferating Dlx2(+)cells were higher in density in the caudal ganglionic eminence (CGE) compared with the MGE, and persisted beyond 35 gw. Consistent with these findings, Sox2, Nkx2.1, Dlx2, and Mash1 protein levels were higher in the ganglionic eminences relative to the cortical VZ/SVZ. The density of gamma-aminobutyric acid-positive (GABA(+)) interneurons was higher in the cortical VZ/SVZ relative to MGE, but Nkx2.1 or Dlx2-expressing GABA(+)cells were more dense in the MGE compared with the cortical VZ/SVZ. The data suggest that the MGE and CGE are the primary source of cortical interneurons. Moreover, their generation continues nearly to the end of pregnancy, which may predispose premature infants to neurobehavioral disorders.
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Encéfalo/embriología , Encéfalo/fisiología , Desarrollo Fetal , Neuronas GABAérgicas/fisiología , Interneuronas/fisiología , Células-Madre Neurales/fisiología , Encéfalo/metabolismo , Recuento de Células , Corteza Cerebral/embriología , Corteza Cerebral/metabolismo , Corteza Cerebral/fisiología , Femenino , Neuronas GABAérgicas/metabolismo , Edad Gestacional , Proteínas de Homeodominio/metabolismo , Humanos , Interneuronas/metabolismo , Ventrículos Laterales/embriología , Ventrículos Laterales/metabolismo , Ventrículos Laterales/fisiología , Masculino , Eminencia Media/embriología , Eminencia Media/fisiología , Células-Madre Neurales/metabolismo , Neurogénesis , Proteínas Nucleares/metabolismo , Embarazo , Tercer Trimestre del Embarazo , Factor Nuclear Tiroideo 1 , Factores de Transcripción/metabolismoRESUMEN
Impairment of moment-to-moment adjustment of cerebral blood flow (CBF) via neurovascular coupling is thought to play a critical role in the genesis of cognitive impairment associated with aging and pathological conditions associated with accelerated cerebromicrovascular aging (e.g., hypertension, obesity). Although previous studies demonstrate that endothelial dysfunction plays a critical role in neurovascular uncoupling in these conditions, the role of endothelial NO mediation in neurovascular coupling responses is not well understood. To establish the link between endothelial function and functional hyperemia, neurovascular coupling responses were studied in mutant mice overexpressing or deficient in endothelial NO synthase (eNOS), and the role of P2Y1 receptors in purinergic glioendothelial coupling was assessed. We found that genetic depletion of eNOS (eNOS(-/-)) and pharmacological inhibition of NO synthesis significantly decreased the CBF responses in the somatosensory cortex evoked by whisker stimulation and by administration of ATP. Overexpression of eNOS enhanced NO mediation of functional hyperemia. In control mice, the selective and potent P2Y1 receptor antagonist MRS2179 attenuated both whisker stimulation-induced and ATP-mediated CBF responses, whereas, in eNOS(-/-) mice, the inhibitory effects of MRS2179 were blunted. Collectively, our findings provide additional evidence for purinergic glio-endothelial coupling during neuronal activity, highlighting the role of ATP-mediated activation of eNOS via P2Y1 receptors in functional hyperemia.
Asunto(s)
Astrocitos/enzimología , Comunicación Celular , Células Endoteliales/enzimología , Hiperemia/enzimología , Microcirculación , Acoplamiento Neurovascular , Óxido Nítrico Sintasa de Tipo III/metabolismo , Receptores Purinérgicos P2Y1/metabolismo , Corteza Somatosensorial/enzimología , Animales , Comunicación Celular/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Hemodinámica , Homeostasis , Hiperemia/genética , Hiperemia/fisiopatología , Mecanotransducción Celular , Ratones Endogámicos C57BL , Ratones Noqueados , Microcirculación/efectos de los fármacos , Acoplamiento Neurovascular/efectos de los fármacos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo III/deficiencia , Óxido Nítrico Sintasa de Tipo III/genética , Agonistas del Receptor Purinérgico P2Y/farmacología , Antagonistas del Receptor Purinérgico P2Y/farmacología , Receptores Purinérgicos P2Y1/efectos de los fármacos , Corteza Somatosensorial/irrigación sanguínea , Corteza Somatosensorial/efectos de los fármacos , Corteza Somatosensorial/fisiopatología , Vibrisas/inervaciónRESUMEN
BACKGROUND: We compared (1) cellular reactive oxygen species (ROS) production, inflammation, and apoptosis of cultured endothelial cells treated with sera and (2) circulating inflammatory measures, antioxidant capacity, vascular biomarkers, and calf muscle hemoglobin oxygen saturation (StO2) in men and women with peripheral artery disease (PAD). A secondary aim was to compare exercise performance and daily ambulatory activity between men and women. We hypothesized that women would have more impaired endothelial cellular ROS, inflammation, and apoptosis than men as well as worse systemic inflammation, antioxidant capacity, vascular biomarkers, calf muscle StO2, exercise performance, and daily ambulatory activity. METHODS: The 148 symptomatic men and women with PAD were characterized on the endothelial effects of circulating factors present in the sera by a cell culture-based bioassay on primary human arterial endothelial cells. Patients were further evaluated by circulating inflammatory and vascular biomarkers, physical examination and medical history, exercise performance, and calf muscle StO2 during exercise, and ambulatory activity was monitored during 1 week. RESULTS: Cellular ROS production was higher in African American women than in men (P = .021), but there was no gender difference in white individuals (P = .537). Men and women were not significantly different on endothelial cell apoptosis (P = .833) and nuclear factor κB activity (P = .465). For circulating factors, additional gender differences were found when comparisons were made within each race. In African Americans, women had higher intercellular adhesion molecule 1 (P = .022) and leptin (P < .001); whereas in white individuals, women had higher matrix metallopeptidase 9 (P = .047), higher vascular cell adhesion molecule 1 (P = .047), and lower hepatocyte growth factor (P = .046). Overall, women had higher apolipoprotein CIII (P = .035), lower pain-free distance (P = .048) and total distance (P < .001) during the 6-minute walk test, shorter time for calf muscle StO2 to reach the minimum value during exercise (P = .027), and slower average cadence (P = .004) during daily ambulation. CONCLUSIONS: African American women with symptomatic PAD have a heightened oxidative status, likely resulting in increased endothelial oxidative stress, compared with men. Furthermore, women exhibit a more pronounced proinflammatory profile of circulating biomarkers as well as more limited peripheral microcirculation, exercise performance, and ambulatory activity than men do. The clinical significance is that women with symptomatic PAD are in greater need than men of clinical intervention to improve oxidative stress, inflammation, and microcirculation, which may in turn have a favorable impact on their lower exercise performance and daily activity.
Asunto(s)
Negro o Afroamericano , Endotelio Vascular/fisiopatología , Mediadores de Inflamación/sangre , Estrés Oxidativo/fisiología , Enfermedad Arterial Periférica/etnología , Enfermedad Arterial Periférica/fisiopatología , Población Blanca , Actividades Cotidianas/clasificación , Anciano , Apoptosis/fisiología , Prueba de Esfuerzo , Femenino , Hemoglobinometría , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/irrigación sanguínea , Especies Reactivas de Oxígeno/sangre , Factores de Riesgo , Factores SexualesRESUMEN
Moment-to-moment adjustment of cerebral blood flow (CBF) to neuronal activity via neurovascular coupling is essential for the maintenance of normal neuronal function. Increased oxidative stress that occurs with aging was shown to impair neurovascular coupling, which likely contributes to a significant age-related decline in higher cortical function, increasing the risk for vascular cognitive impairment. Resveratrol is a polyphenolic compound that exerts significant antiaging protective effects in large vessels, but its effects on the cerebromicrovasculature remain poorly defined. The present study was undertaken to investigate the capacity of resveratrol to improve neurovascular coupling in aging. In aged (24-mo-old) C57BL/6 mice N(ω)-nitro-l-arginine methyl ester-sensitive, nitric oxide-mediated CBF responses to whisker stimulation and to the endothelium-dependent dilator acethylcholine (ACh) were impaired compared with those in young (3-mo-old) mice. Treatment of aged mice with resveratrol rescued neurovascular coupling and ACh-induced responses, which was associated with downregulation of cortical expression of NADPH oxidase and decreased levels of biomarkers of oxidative/nitrative stress (3-nitrotyrosine, 8-isoprostanes). Resveratrol also attenuated age-related increases in reactive oxygen species (ROS) production in cultured cerebromicrovascular endothelial cells (DCF fluorescence, flow cytometry). In conclusion, treatment with resveratrol rescues cortical neurovascular coupling responses to increased neuronal activity in aged mice, likely by restoring cerebromicrovascular endothelial function via downregulation of NADPH oxidase-derived ROS production. Beneficial cerebromicrovascular effects of resveratrol may contribute to its protective effects on cognitive function in aging.
Asunto(s)
Envejecimiento/fisiología , Cerebro/irrigación sanguínea , Endotelio Vascular/efectos de los fármacos , Microcirculación/efectos de los fármacos , Estilbenos/farmacología , Vasodilatación/efectos de los fármacos , Animales , Demencia Vascular/prevención & control , Endotelio Vascular/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Microcirculación/fisiología , NADPH Oxidasas/metabolismo , Estrés Oxidativo/fisiología , Especies Reactivas de Oxígeno/metabolismo , Resveratrol , Vasodilatadores/farmacologíaRESUMEN
Whole brain radiation therapy (WBRT) induces profound cerebral microvascular rarefaction throughout the hippocampus. Despite the vascular loss and localized cerebral hypoxia, angiogenesis fails to occur, which subsequently induces long-term deficits in learning and memory. The mechanisms underlying the absence of vessel recovery after WBRT are unknown. We tested the hypotheses that vascular recovery fails to occur under control conditions as a result of loss of angiogenic drive in the circulation, chronic tissue inflammation, and/or impaired endothelial cell production/recruitment. We also tested whether systemic hypoxia, which is known to promote vascular recovery, reverses these chronic changes in inflammation and endothelial cell production/recruitment. Ten-week-old C57BL/6 mice were subjected to a clinical series of fractionated WBRT: 4.5-Gy fractions 2 times/wk for 4 wk. Plasma from radiated mice increased in vitro endothelial cell proliferation and adhesion compared with plasma from control mice, indicating that WBRT did not suppress the proangiogenic drive. Analysis of cytokine levels within the hippocampus revealed that IL-10 and IL-12(p40) were significantly increased 1 mo after WBRT; however, systemic hypoxia did not reduce these inflammatory markers. Enumeration of endothelial progenitor cells (EPCs) in the bone marrow and circulation indicated that WBRT reduced EPC production, which was restored with systemic hypoxia. Furthermore, using a bone marrow transplantation model, we determined that bone marrow-derived endothelial-like cells home to the hippocampus after systemic hypoxia. Thus, the loss of production and homing of EPCs have an important role in the prolonged vascular rarefaction after WBRT.