RESUMEN
With advancing age, the cerebral vasculature becomes dysfunctional, and this dysfunction is associated with cognitive decline. However, the initiating cause of these age-related cerebrovascular impairments remains incompletely understood. A characteristic feature of the aging vasculature is the increase in stiffness of the large elastic arteries. This increase in arterial stiffness is associated with elevated pulse pressure and blood flow pulsatility in the cerebral vasculature. Evidence from both humans and rodents supports that increases in large elastic artery stiffness are associated with cerebrovascular impairments. These impacts on cerebrovascular function are wide-ranging and include reductions in global and regional cerebral blood flow, cerebral small vessel disease, endothelial cell dysfunction, and impaired perivascular clearance. Furthermore, recent findings suggest that the relationship between arterial stiffness and cerebrovascular function may be influenced by genetics, specifically APOE and NOTCH genotypes. Given the strength of the evidence that age-related increases in arterial stiffness have deleterious impacts on the brain, interventions that target arterial stiffness are needed. The purpose of this review is to summarize the evidence from human and rodent studies, supporting the role of increased arterial stiffness in age-related cerebrovascular impairments.
Asunto(s)
Rigidez Vascular , Humanos , Rigidez Vascular/fisiología , Presión Sanguínea/fisiología , Hemodinámica , Arterias , Envejecimiento , Circulación Cerebrovascular/fisiologíaRESUMEN
As females age, they transition through menopause, experiencing a decrease in estrogen and an increase in cardiovascular and neurodegenerative disease risk. Most standard rodent chows contain phytoestrogen-rich soybean meal, which can mimic the effects of estrogen. Understanding the impact of this soybean meal on vascular outcomes is crucial to proper experimental design. Thus, this study aimed to compare the effects of standard and soy-free chows on cerebral artery endothelial function and cognitive function in ovariectomized mice. Young female C57Bl/6J mice (n = 43; â¼6 mo) were randomly assigned to three groups: sham, ovariectomy (OVX), or ovariectomy on a diet containing soy (OVX + Soy). In posterior cerebral arteries, the OVX mice had a 27% lower maximal response to insulin compared with the sham mice. The OVX + Soy mice had a 27% greater maximal vasodilation to insulin compared with the OVX mice and there were no differences in vasodilation between the OVX + Soy and sham groups. The group differences in vasodilation were mediated by differences in nitric oxide bioavailability. The OVX + Soy mice also had greater insulin receptor gene expression in cerebral arteries compared with the OVX mice. However, no differences in aortic or cerebral artery stiffness were observed between groups. Interestingly, the OVX + Soy group scored better on nesting behavior compared with both sham and OVX groups. In summary, we found that ovariectomy impairs insulin-mediated vasodilation in cerebral arteries, but a diet containing soy mitigates these effects. These findings highlight the importance of considering dietary soy when performing vascular and behavioral tests in mice, particularly in females.NEW & NOTEWORTHY To properly design experiments, we must consider how variables like diet impact our outcomes, particularly the effects of soy on females. We found that cerebral artery vasodilation in response to insulin was impaired in ovariectomized female mice compared with intact shams. However, ovariectomized mice fed a soy diet had a preserved cerebral artery insulin-mediated vasodilation. These results highlight that the effects of diet on vascular function may explain inconsistencies found between studies.
Asunto(s)
Insulinas , Enfermedades Neurodegenerativas , Ratones , Femenino , Animales , Humanos , Dieta , Estrógenos , Arterias Cerebrales , OvariectomíaRESUMEN
Nonnutritive sweeteners (NNSs) and low-calorie sweeteners (LCSs) are commonly used as sugar substitutes. Many popular media Web sites caution against the use of these sweeteners because of their potential adverse effects such as inflammation; however, there are limited supporting data. A Medline search of articles published between 2010 and 2020 was conducted, resulting in 833 articles, of which 12 relevant studies were included in this review. Acute adverse effects associated with the consumption of NNSs and LCSs are rare. A few studies cite reports of acute adverse effects, including mild gastrointestinal disturbance, headaches, lightheadedness, hypersensitivity reactions, impaired spatial orientation, depression, and pain. Little scientific evidence has been reported in the literature since 2010 to support these warning statements to consumers about acute adverse effects to NNSs and LCSs.
Asunto(s)
Edulcorantes no Nutritivos , Edulcorantes , Humanos , Edulcorantes/efectos adversos , Ingestión de Energía , Edulcorantes no Nutritivos/efectos adversos , Cefalea/inducido químicamente , InflamaciónRESUMEN
OBJECTIVES: Our aim was to identify self-reported stressors and coping mechanisms during the 2020-2021 application cycle by dermatology residency applicants. We hypothesized that coronavirus disease 2019 (COVID-19) would be the most reported stressor. METHODS: During the 2020-2021 application season, the Mayo Clinic Florida Dermatology residency program sent a supplemental application to each applicant requesting that they describe a challenging life situation and how they handled it. Comparisons of self-reported stressors and self-expressed coping mechanisms according to sex, race, and geographic region were performed. RESULTS: The most common stressors reported were academic (18.4%), family crisis (17.7%), and COVID-19 (10.5%). The most frequent coping mechanisms expressed were perseverance (22.3%), seeking community (13.7%), and resilience (11.5%). The coping mechanism of diligence was observed more often in females than in males (2.8% vs 0.0%, P = 0.045). First in medicine was more often observed in Black or African American students (12.5% vs 0%, P = 0.001), immigrant experience was more often observed in Black or African American and Hispanic students (16.7% and 11.8% vs 3.1%, P = 0.021), and natural disaster was reported more often in Hispanic students (26.5% vs 0.5%, P < 0.001) as compared with White applicants. By geography, applicants in the northeastern United States were more likely to report the COVID-19 pandemic as a stressor (19.5%, P = 0.049), and the natural disaster stressor was more often reported by applicants from outside the continental United States (45.5%, P < 0.001). CONCLUSIONS: Stressors reported by dermatology applicants in the 2020-2021 cycle included academic, family crisis, and the COVID-19 pandemic. The type of stressor reported varied by race/ethnicity and geographic location of the applicant.
Asunto(s)
COVID-19 , Dermatología , Internado y Residencia , Femenino , Masculino , Humanos , Autoinforme , COVID-19/epidemiología , Pandemias , Adaptación PsicológicaRESUMEN
With the increasing appreciation for sex as a biological variable and the inclusion of female mice in research, it is important to understand the influence of the estrous cycle on physiological function. Sex hormones are known to modulate vascular function, but the effects of the mouse estrous cycle phase on arterial stiffness, endothelial function, and arterial estrogen receptor expression remain unknown. In 23 female C57BL/6 mice (6 mo of age), we determined the estrous cycle stage via vaginal cytology and plasma hormone concentrations. Aortic stiffness, assessed by pulse wave velocity, was lower during the estrus phase compared with diestrus. In ex vivo assessment of isolated pressurized mesenteric and posterior cerebral arteries, the responses to acetylcholine, insulin, and sodium nitroprusside, as well as nitric oxide-mediated dilation, were not different between estrous cycle phases. In the aorta, expression of phosphorylated estrogen receptor-α was higher for mice in estrus compared with mice in proestrus. In the cerebral arteries, gene expression for estrogen receptor-ß (Esr2) was lowest for mice in estrus compared with diestrus and proestrus. These results demonstrate that the estrus phase is associated with lower in vivo large artery stiffness in mice. In contrast, ex vivo resistance artery endothelial function is not different between estrous cycle phases. Estrogen receptor expression is modulated by the estrus cycle in an artery-dependent manner. These results suggest that the estrous cycle phase should be considered when measuring in vivo arterial stiffness in young female mice.NEW & NOTEWORTHY To design rigorous vascular research studies using young female rodents, the influence of the estrous cycle on vascular function must be known. We found that in vivo aortic stiffness was lower during estrus compared with the diestrus phase in female mice. In contrast, ex vivo mesenteric and cerebral artery endothelial function did not differ between estrous cycle stages. These results suggest that the estrous cycle stage should be accounted for when measuring in vivo arterial stiffness.
Asunto(s)
Rigidez Vascular , Ratones , Femenino , Animales , Receptores de Estrógenos , Análisis de la Onda del Pulso , Ratones Endogámicos C57BL , Ciclo Estral/fisiología , Estrógenos , ArteriasRESUMEN
The purpose of this study was to evaluate the effects of performance-based feedback delivered via email on teacher candidates' implementation of a multiple stimulus without replacement (MSWO) preference assessment with an adult confederate. Six participants enrolled in a special education teacher preparation program were recruited to participate. After exposure to an introductory MSWO training video, participant fidelity of MSWO administration was measured. Following baseline, performance feedback was delivered via e-mail to each participant after the completion of each research session. Results indicate that performance feedback delivered via e-mail improved fidelity of implementation for all six participants. Implications and future directions are discussed. Supplementary Information: The online version contains supplementary material available at 10.1007/s10864-022-09496-z.
RESUMEN
There are no effective treatments available to halt or reverse the progression of age-related cognitive decline and Alzheimer's disease. Thus, there is an urgent need to understand the underlying mechanisms of disease etiology and progression to identify novel therapeutic targets. Age-related changes to the vasculature, particularly increases in stiffness of the large elastic arteries, are now recognized as important contributors to brain aging. There is a growing body of evidence for an association between greater large artery stiffness and cognitive impairment among both healthy older adults and patients with Alzheimer's disease. However, studies in humans are limited to only correlative evidence, whereas animal models allow researchers to explore the causative mechanisms linking arterial stiffness to neurocognitive dysfunction and disease. Recently, several rodent models of direct modulation of large artery stiffness and the consequent effects on the brain have been reported. Common outcomes among these models have emerged, including evidence that greater large artery stiffness causes cerebrovascular dysfunction associated with increased oxidative stress and inflammatory signaling. The purpose of this mini-review is to highlight the recent findings associating large artery stiffness with deleterious brain outcomes, with a specific focus on causative evidence obtained from animal models. We will also discuss the gaps in knowledge that remain in our understanding of how large artery stiffness affects brain function and disease outcomes.
Asunto(s)
Encéfalo/irrigación sanguínea , Circulación Cerebrovascular , Trastornos Cerebrovasculares/etiología , Cognición , Disfunción Cognitiva/etiología , Enfermedad Arterial Periférica/complicaciones , Rigidez Vascular , Factores de Edad , Animales , Trastornos Cerebrovasculares/fisiopatología , Envejecimiento Cognitivo/psicología , Disfunción Cognitiva/fisiopatología , Disfunción Cognitiva/psicología , Modelos Animales de Enfermedad , Humanos , Enfermedad Arterial Periférica/fisiopatología , Factores de RiesgoRESUMEN
OBJECTIVE: Individual residency programs often struggle to keep pace with scientific advances and new training requirements. Integrating a modern neuroscience perspective into the clinical practice of psychiatry is particularly emblematic of these challenges. The National Neuroscience Curriculum Initiative (NNCI) was established in 2013 to develop a comprehensive set of shared, open-access resources for teaching neuroscience in psychiatry. METHODS: The NNCI developed a collaborative, team-based approach with a peer-review process for generating and reviewing content. Teaching resources have included interactive sessions for the classroom paired with a comprehensive facilitator's guide. Brief accessible reviews and short videos have been developed for self-study and teaching in clinical settings. Dissemination efforts have included hands-on training for educators through national workshops. All resources are freely available on the NNCI website. Outcome measures have included the number of educational resources developed, feedback from workshop attendees, the number of US psychiatry residency programs who have adopted NNCI resources, as well as analytics from the NNCI website. RESULTS: To date, the NNCI has developed over 150 teaching sessions, reflecting the work of 129 authors from 49 institutions. The NNCI has run over 50 faculty development workshops in collaboration with numerous national and international organizations. Between March 2015 and June 2019, the website (www.NNCIonline.org) has hosted 48,640 unique users from 161 countries with 500,953 page views. More than 200 psychiatry training programs have reported implementing NNCI teaching materials. CONCLUSIONS: This multisite collaborative provides a model for integrating cutting-edge science into medical education and the practice of medicine more broadly.
Asunto(s)
Curriculum , Educación Médica , Neurociencias/educación , Psiquiatría/educación , Adulto , Curriculum/normas , Educación Médica/normas , Humanos , Colaboración IntersectorialRESUMEN
Age-related vascular dysfunction in large elastic and resistance arteries is associated with reductions in microvascular perfusion and elevations in blood pressure. Recent evidence indicates that telomere uncapping-induced senescence in vascular cells may be an important source of oxidative stress and vascular dysfunction in aging, but the causal relationship between these processes has yet to be elucidated. To test this important unexplored hypothesis, we measured arterial senescence signaling and oxidative stress, carotid and mesenteric artery endothelium-dependent vasodilatory capacity, markers of mesenteric microvascular perfusion and endothelial glycocalyx deterioration, and blood pressure in a novel mouse model of Cre-inducible whole body Trf2 deletion and telomere uncapping. Trf2 deletion led to a 320% increase in arterial senescence signaling (Pâ¯<â¯.05). There was a concurrent 29% and 22% reduction in peak endothelium-dependent vasodilation in carotid and mesenteric arteries, respectively, as well as a 63% reduction in mesenteric microvascular endothelial glycocalyx thickness (all Pâ¯≤â¯.01). Mesenteric microvascular perfusion was reduced by 8% and systolic blood pressure was increased by 9% following Trf2 deletion (both Pâ¯<â¯.05). Trf2 deletion also led to a pro-oxidative arterial phenotype characterized by increased in NADPH oxidase gene expression; a 210% increase in superoxide levels that was partly dependent on NADPH oxidase activity; and an oxidative stress mediated reduction in carotid artery vasodilation (all Pâ¯≤â¯.05). Collectively, our findings demonstrate that induced Trf2 deletion leads to telomere uncapping, increased senescence signaling, and oxidative stress mediated functional impairments in the vasculature similar to those seen in human aging.
Asunto(s)
Envejecimiento/metabolismo , Arterias/metabolismo , Senescencia Celular , Eliminación de Gen , Estrés Oxidativo , Transducción de Señal , Telómero/metabolismo , Proteína 2 de Unión a Repeticiones Teloméricas/deficiencia , Tejido Adiposo/metabolismo , Animales , Presión Sanguínea , Peso Corporal , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Glicocálix/metabolismo , Ratones , Microvasos/metabolismo , Perfusión , Fenotipo , Homeostasis del Telómero , Proteína 2 de Unión a Repeticiones Teloméricas/metabolismo , VasodilataciónRESUMEN
OBJECTIVE: Accumulating evidence suggests the vascular endothelium plays a fundamental role in the pathophysiology of obesity by regulating the functional status of white adipose and systemic metabolism. Robo4 is expressed specifically in endothelial cells and increases vascular stability and inhibits angiogenesis. We sought to determine the role of Robo4 in modulating cardiometabolic function in response to high-fat feeding. METHODS: We examined exercise capacity, glucose tolerance, and white adipose tissue artery gene expression, endothelium-dependent dilation (EDD), and angiogenesis in wild type and Robo4 knockout (KO) mice fed normal chow (NC) or a high-fat diet (HFD). RESULTS: We found Robo4 deletion enhances exercise capacity in NC-fed mice and HFD markedly increased the expression of the Robo4 ligand, Slit2, in white adipose tissue. Deletion of Robo4 increased angiogenesis in white adipose tissue and protected against HFD-induced impairments in white adipose artery vasodilation and glucose intolerance. CONCLUSIONS: We demonstrate a novel functional role for Robo4 in endothelial cell function and metabolic homeostasis in white adipose tissue, with Robo4 deletion protecting against endothelial and metabolic dysfunction associated with a HFD. Our findings suggest that Robo4-dependent signaling pathways may be a novel target in anti-obesity therapy.
Asunto(s)
Tejido Adiposo Blanco , Arterias , Grasas de la Dieta/efectos adversos , Endotelio Vascular , Eliminación de Gen , Regulación de la Expresión Génica/efectos de los fármacos , Receptores de Superficie Celular , Tejido Adiposo Blanco/irrigación sanguínea , Tejido Adiposo Blanco/metabolismo , Tejido Adiposo Blanco/patología , Animales , Arterias/metabolismo , Arterias/patología , Grasas de la Dieta/farmacología , Endotelio Vascular/metabolismo , Endotelio Vascular/patología , Péptidos y Proteínas de Señalización Intercelular/biosíntesis , Péptidos y Proteínas de Señalización Intercelular/genética , Ratones , Ratones Noqueados , Neovascularización Fisiológica/efectos de los fármacos , Neovascularización Fisiológica/genética , Proteínas del Tejido Nervioso/biosíntesis , Proteínas del Tejido Nervioso/genética , Receptores de Superficie Celular/biosíntesis , Receptores de Superficie Celular/deficiencia , Vasodilatación/efectos de los fármacos , Vasodilatación/genéticaRESUMEN
NEW FINDINGS: What is the central question of this study? Greater large artery stiffness is associated with dysfunctional resistance artery vasodilatory responses, impaired memory and greater risk of Alzheimer's disease. However, it is unknown whether stiffer large arteries affect cerebral and skeletal muscle feed artery responses to vasoconstrictors. What is the main finding and its importance? In a mouse model with greater large artery stiffness (Eln+/- ), we find an exacerbated vasoconstrictor response to angiotensin II in cerebral arteries, but not skeletal muscle feed arteries, thus implicating altered cerebral artery angiotensin II responsiveness in the poor brain outcomes associated with greater large artery stiffness. ABSTRACT: Greater stiffness of the large elastic arteries is associated with end-organ damage and dysfunction. At the same time, resistance artery vasoconstrictor responsiveness influences vascular tone and organ blood flow. However, it is unknown whether large elastic artery stiffness modulates the responsiveness to vasoconstrictors in resistance arteries of the cerebral or skeletal muscle circulations. We previously described the elastin haploinsufficient (Eln+/- ) mouse as a model with greater aortic stiffness, but with similar cerebral and skeletal muscle feed artery stiffness to wild-type (Eln+/+ ) mice. Here, we used this model to examine the relationship between large elastic artery stiffness and resistance artery vasoconstrictor responses. In middle cerebral arteries (MCAs), vasoconstriction in response to angiotensin II (Ang II) was â¼40% greater in Eln+/- compared with Eln+/+ mice (P = 0.02), and this group difference was ameliorated by losartan, indicating a role for Ang II type 1 receptors (AT1Rs). In gastrocnemius feed arteries, Eln+/- and Eln+/+ mice did not differ in the response to Ang II. In addition, the vasoconstrictor responses to noradrenaline, endothelin-1 and potassium chloride were not different between Eln+/- and Eln+/+ mice for either MCAs or gastrocnemius feed arteries. The MCA AT1R gene expression did not differ between groups, whereas Ang II type 2 receptor gene expression was â¼50% lower in MCAs from Eln+/- versus Eln+/+ mice (P = 0.01). In conclusion, greater large elastic artery stiffness is associated with an exacerbated vasoconstriction response to Ang II in cerebral arteries, but is not associated with the responses to other vasoconstrictors in either cerebral or skeletal muscle feed arteries.
Asunto(s)
Arterias Cerebrales/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Rigidez Vascular/efectos de los fármacos , Vasoconstricción/efectos de los fármacos , Vasoconstrictores/farmacología , Angiotensina II/farmacología , Animales , Arterias Cerebrales/metabolismo , Arterias Cerebrales/fisiopatología , Modelos Animales de Enfermedad , Endotelina-1/metabolismo , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Endotelio Vascular/fisiopatología , Losartán/farmacología , Masculino , Ratones , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatología , Norepinefrina/metabolismo , Receptor de Angiotensina Tipo 1/metabolismo , Rigidez Vascular/fisiología , Vasoconstricción/fisiologíaRESUMEN
PURPOSE: Drug-eluting balloon catheters (DEBc) coated with paclitaxel (PTX) have been associated with potential safety concerns. An efficacious but less toxic balloon coating may reduce these outcomes. We evaluated a novel DEBc, Epi-Solve, coated with metacept-3 (MCT-3), a member of the histone deacetylase inhibitor (HDACi) class of epigenetic agents, in a large animal model of neointimal hyperplasia (NIH). METHODS: Plain balloon angioplasty (PABA) catheters were ultrasonically coated with MCT-3 to generate Epi-Solve DEBc. An ovine model of NIH formation was established utilising partial left common carotid artery (LCA) ligation. Twenty-eight days post neointima (NI) induction, PABA, Epi-Solve or PTX-coated DEBc were deployed at the site of induced NI formation. Twenty-eight days post-intervention, ligated vessels were evaluated for attenuation of NI formation, gene expression profiles and immunohistochemical analysis. RESULTS: Epi-Solve DEBc demonstrated attenuation of NIH over no intervention and a trend to inhibition of NIH over PABA. Gene expression analysis and immunohistochemical studies identified significant anti-proliferative and anti-inflammatory signatures and reduced vascular endothelial cell activation compared to PABA. CONCLUSIONS: Epi-Solve is a novel HDACi-coated DEBc which demonstrates significant anti-proliferative and anti-inflammatory signatures and reduced vascular endothelial cell activation compared to PABA in an ovine model and may afford endothelial protection.
Asunto(s)
Angioplastia de Balón/instrumentación , Enfermedades de las Arterias Carótidas/terapia , Arteria Carótida Común/patología , Materiales Biocompatibles Revestidos , Epigénesis Genética/efectos de los fármacos , Inhibidores de Histona Desacetilasas/administración & dosificación , Neointima , Dispositivos de Acceso Vascular , Animales , Enfermedades de las Arterias Carótidas/genética , Enfermedades de las Arterias Carótidas/metabolismo , Enfermedades de las Arterias Carótidas/patología , Arteria Carótida Común/metabolismo , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Diseño de Equipo , Femenino , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales de la Vena Umbilical Humana/patología , Humanos , Mediadores de Inflamación/metabolismo , Paclitaxel/administración & dosificación , Oveja Doméstica , Factores de TiempoRESUMEN
Although most telomere biology research continues to focus on telomere shortening, there is increasing evidence that telomere deprotection, or "uncapping," is more biologically and possibly clinically important. Telomeres form t-loops to prevent the chromosome ends from appearing as a double-stranded DNA break and initiating a DNA damage response. Breakdown of the t-loop structure, referred to as uncapping, can lead to cellular senescence, increased oxidative stress, and inflammation in tissues. In this review, we describe how telomere uncapping potentially leads to age-related vascular dysfunction and increased cellular senescence, oxidative stress, and inflammation. Importantly, we present evidence to argue that telomere uncapping is more biologically relevant than telomere shortening and a better marker of vascular aging and target for antiaging interventions.
Asunto(s)
Vasos Sanguíneos/metabolismo , Senescencia Celular , Homeostasis del Telómero , Telómero/metabolismo , Animales , Vasos Sanguíneos/crecimiento & desarrollo , Humanos , Telómero/genéticaRESUMEN
OBJECTIVE: In the first year of training, psychiatry residents progress from direct supervision to indirect supervision but factors predicting time to transition between these levels of supervision are unknown. This study aimed to examine times for transition to indirect levels of supervision and to identify resident factors associated with slower progression. METHODS: The authors compiled data from training files from years 2011-2015, including licensing exam scores, age, gender, medical school, month of first inpatient psychiatry rotation, and transition times between levels of supervision. Correlational analysis examined the relationship between these factors. Univariate analysis further examined the relationship between medical school training and transition times between supervision levels. RESULTS: Among the factors studied, only international medical school training was positively correlated with time to transition to indirect supervision and between levels of indirect supervision. CONCLUSIONS: International medical graduate (IMG) interns in psychiatry training may benefit from additional training and support to reach competencies required for the transition to indirect supervision.
Asunto(s)
Competencia Clínica , Médicos Graduados Extranjeros/educación , Internado y Residencia/organización & administración , Psiquiatría/educación , Adulto , Femenino , Humanos , Masculino , Proyectos Piloto , Factores de TiempoRESUMEN
BACKGROUND: Cerebral cavernous malformation (CCM) is a hemorrhagic stroke disease affecting up to 0.5% of North Americans that has no approved nonsurgical treatment. A subset of patients have a hereditary form of the disease due primarily to loss-of-function mutations in KRIT1, CCM2, or PDCD10. We sought to identify known drugs that could be repurposed to treat CCM. METHODS AND RESULTS: We developed an unbiased screening platform based on both cellular and animal models of loss of function of CCM2. Our discovery strategy consisted of 4 steps: an automated immunofluorescence and machine-learning-based primary screen of structural phenotypes in human endothelial cells deficient in CCM2, a secondary screen of functional changes in endothelial stability in these same cells, a rapid in vivo tertiary screen of dermal microvascular leak in mice lacking endothelial Ccm2, and finally a quaternary screen of CCM lesion burden in these same mice. We screened 2100 known drugs and bioactive compounds and identified 2 candidates, cholecalciferol (vitamin D3) and tempol (a scavenger of superoxide), for further study. Each drug decreased lesion burden in a mouse model of CCM vascular disease by ≈50%. CONCLUSIONS: By identifying known drugs as potential therapeutics for CCM, we have decreased the time, cost, and risk of bringing treatments to patients. Each drug also prompts additional exploration of biomarkers of CCM disease. We further suggest that the structure-function screening platform presented here may be adapted and scaled to facilitate drug discovery for diverse loss-of-function genetic vascular disease.
Asunto(s)
Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Modelos Animales de Enfermedad , Reposicionamiento de Medicamentos/métodos , Hemangioma Cavernoso del Sistema Nervioso Central/tratamiento farmacológico , Animales , Células Cultivadas , Neoplasias del Sistema Nervioso Central/patología , Colecalciferol/farmacología , Colecalciferol/uso terapéutico , Ensayos de Selección de Medicamentos Antitumorales/métodos , Células Endoteliales/efectos de los fármacos , Células Endoteliales/patología , Depuradores de Radicales Libres/farmacología , Depuradores de Radicales Libres/uso terapéutico , Hemangioma Cavernoso del Sistema Nervioso Central/patología , Humanos , Ratones , Ratones Noqueados , Ratones Transgénicos , Resultado del TratamientoRESUMEN
The efficient and selective catalytic reduction of CO2 is a highly promising process for both of the storage of renewable energy as well as the production of valuable chemical feedstocks. In this work, we show that the addition of an ionic liquid, 1-butyl-3-methylimidazolium tetrafluoroborate, in an aprotic electrolyte containing a proton source and FeTPP, promotes the in situ formation of the [Fe(0) TPP](2-) homogeneous catalyst at a less negative potential, resulting in lower overpotentials for the CO2 reduction (670â mV) and increased kinetics of electron transfer. This co-catalysis exhibits high Faradaic efficiency for CO production (93 %) and turnover number (2 740 000 after 4â hour electrolysis), with a four-fold increase in turnover frequency (TOF) when compared with the standard system without the ionic liquid.
RESUMEN
Cardiovascular disease (CVD) is the leading cause of death in the United States and aging is a major risk factor for CVD development. One of the major age-related arterial phenotypes thought to be responsible for the development of CVD in older adults is endothelial dysfunction. Endothelial function is modulated by traditional CVD risk factors in young adults, but advancing age is independently associated with the development of vascular endothelial dysfunction. This endothelial dysfunction results from a reduction in nitric oxide bioavailability downstream of endothelial oxidative stress and inflammation that can be further modulated by traditional CVD risk factors in older adults. Greater endothelial oxidative stress with aging is a result of augmented production from the intracellular enzymes NADPH oxidase and uncoupled eNOS, as well as from mitochondrial respiration in the absence of appropriate increases in antioxidant defenses as regulated by relevant transcription factors, such as FOXO. Interestingly, it appears that NFkB, a critical inflammatory transcription factor, is sensitive to this age-related endothelial redox change and its activation induces transcription of pro-inflammatory cytokines that can further suppress endothelial function, thus creating a vicious feed-forward cycle. This review will discuss the two macro-mechanistic processes, oxidative stress and inflammation, that contribute to endothelial dysfunction with advancing age as well as the cellular and molecular events that lead to the vicious cycle of inflammation and oxidative stress in the aged endothelium. Other potential mediators of this pro-inflammatory endothelial phenotype are increases in immune or senescent cells in the vasculature. Of note, genomic instability, telomere dysfunction or DNA damage has been shown to trigger cell senescence via the p53/p21 pathway and result in increased inflammatory signaling in arteries from older adults. This review will discuss the current state of knowledge regarding the emerging concepts of senescence and genomic instability as mechanisms underlying oxidative stress and inflammation in the aged endothelium. Lastly, energy sensitive/stress resistance pathways (SIRT-1, AMPK, mTOR) are altered in endothelial cells and/or arteries with aging and these pathways may modulate endothelial function via key oxidative stress and inflammation-related transcription factors. This review will also discuss what is known about the role of "energy sensing" longevity pathways in modulating endothelial function with advancing age. With the growing population of older adults, elucidating the cellular and molecular mechanisms of endothelial dysfunction with age is critical to establishing appropriate and measured strategies to utilize pharmacological and lifestyle interventions aimed at alleviating CVD risk. This article is part of a Special Issue entitled "SI: CV Aging".
Asunto(s)
Senescencia Celular , Células Endoteliales/patología , Animales , Enfermedades Cardiovasculares/patología , Endotelio Vascular/patología , Metabolismo Energético , Inestabilidad Genómica , HumanosRESUMEN
KEY POINTS: Increased large artery stiffness is a hallmark of arterial dysfunction with advancing age and is also present in other disease conditions such as diabetes. Increased large artery stiffness is correlated with resistance artery dysfunction in humans. Using a mouse model of altered arterial elastin content, this is the first study to examine the cause-and-effect relationship between large artery stiffness and peripheral resistance artery function. Our results indicate that mice with genetically greater large artery stiffness have impaired cerebral artery endothelial function, but generally preserved skeletal muscle feed artery endothelial function. The mechanisms for impaired cerebral artery endothelial function are reduced nitric oxide bioavailability and increased oxidative stress. These findings suggest that interventions that target large artery stiffness may be important to reduce disease risk associated with cerebral artery dysfunction in conditions such as advancing age. ABSTRACT: Advancing age as well as diseases such as diabetes are characterized by both increased large artery stiffness and impaired peripheral artery function. It has been hypothesized that greater large artery stiffness causes peripheral artery dysfunction; however, a cause-and-effect relationship has not previously been established. We used elastin heterozygote mice (Eln(+/-) ) as a model of increased large artery stiffness without co-morbidities unrelated to the large artery properties. Aortic stiffness, measured by pulse wave velocity, was â¼35% greater in Eln(+/-) mice than in wild-type (Eln(+/+) ) mice (P = 0.04). Endothelium-dependent dilatation (EDD), assessed by the maximal dilatation to acetylcholine, was â¼40% lower in Eln(+/-) than Eln(+/+) mice in the middle cerebral artery (MCA, P < 0.001), but was similar between groups in the gastrocnemius feed arteries (GFA, P = 0.79). In the MCA, EDD did not differ between groups after incubation with the nitric oxide (NO) synthase inhibitor N(ω) -nitro-l-arginine methyl ester (P > 0.05), indicating that lower NO bioavailability contributed to the impaired EDD in Eln(+/-) mice. Superoxide production and content of the oxidative stress marker nitrotyrosine was higher in MCAs from Eln(+/-) compared with Eln(+/+) mice (P < 0.05). In the MCA, after incubation with the superoxide scavenger TEMPOL, maximal EDD improved by â¼65% in Eln(+/-) (P = 0.002), but was unchanged in Eln(+/+) mice (P = 0.17). These results indicate that greater large artery stiffness has a more profound effect on endothelial function in cerebral arteries compared with skeletal muscle feed arteries. Greater large artery stiffness can cause cerebral artery endothelial dysfunction by reducing NO bioavailability and increasing oxidative stress.
Asunto(s)
Arterias Cerebrales/fisiopatología , Endotelio Vascular/fisiopatología , Músculo Esquelético/irrigación sanguínea , Rigidez Vascular/fisiología , Animales , Arterias Cerebrales/efectos de los fármacos , Modelos Animales de Enfermedad , Elastina/genética , Elastina/metabolismo , Endotelio Vascular/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Indometacina/farmacología , Ratones , Ratones Noqueados , NG-Nitroarginina Metil Éster/farmacología , Resistencia Vascular/efectos de los fármacos , Resistencia Vascular/fisiología , Rigidez Vascular/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiologíaRESUMEN
The critical influence of the white adipose tissue (WAT) on metabolism is well-appreciated in obesity, but adipose tissue dysfunction as a mechanism underlying age-associated metabolic dysfunction requires elucidation. To explore this possibility, we assessed metabolism and measures of epididymal (e)WAT mitochondria and artery function in young (6.1 ± 0.4 months) and old (29.6 ± 0.2 months) B6D2F1 mice. There were no group differences in average daily oxygen consumption, fasted blood glucose or plasma free fatty acids, but fasted plasma insulin and the homeostatic model assessment of insulin resistance (HOMA-IR%) were higher in the old (â¼50-85%, P < 0.05). Tissue mass (P < 0.05) and adipocyte area were lower (â¼60%) (P < 0.01) and fibrosis was greater (sevenfold, P < 0.01) in eWAT with older age. The old also exhibited greater liver triglycerides (â¼60%, P < 0.05). The mitochondrial respiratory oxygen flux after the addition of glutamate and malate (GM), adenosine diphosphate (d), succinate (S) and octanoyl carnitine (O) were one- to twofold higher in eWAT of old mice (P < 0.05). Despite no change in the respiratory control ratio, substrate control ratios of GMOd/GMd and GMOSd/GMd were â¼30-40% lower in old mice (P < 0.05) and were concomitant with increased nitrotyrosine (P < 0.05) and reduced expression of brown adipose markers (P < 0.05). Ageing reduced vascularity (â¼50%, P < 0.01), angiogenic capacity (twofold, P < 0.05) and expression of vascular endothelial growth factor (â¼50%, P < 0.05) in eWAT. Finally, endothelium-dependent dilation was lower (P < 0.01) in isolated arteries from eWAT arteries of the old mice. Thus, metabolic dysfunction with advancing age occurs in concert with dysfunction in the adipose tissue characterized by both mitochondrial and arterial dysfunction.