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1.
FASEB J ; 38(1): e23325, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38117486

RESUMO

Obesity is driven by an imbalance between caloric intake and energy expenditure, causing excessive storage of triglycerides in adipose tissue at different sites around the body. Increased visceral adipose tissue (VAT) is associated with diabetes, while pericardial adipose tissue (PAT) is associated with cardiac pathology. Adipose tissue can expand either through cellular hypertrophy or hyperplasia, with the former correlating with decreased metabolic health in obesity. The aim of this study was to determine how VAT and PAT remodel in response to obesity, stress, and exercise. Here we have used the male obese Zucker rats, which carries two recessive fa alleles that result in the development of hyperphagia with reduced energy expenditure, resulting in morbid obesity and leptin resistance. At 9 weeks of age, a group of lean (Fa/Fa or Fa/fa) Zucker rats (LZR) and obese (fa/fa) Zucker rats (OZR) were treated with unpredictable chronic mild stress or exercise for 8 weeks. To determine the phenotype for PAT and VAT, tissue cellularity and gene expression were analyzed. Finally, leptin signaling was investigated further using cultured 3T3-derived adipocytes. Tissue cellularity was determined following hematoxylin and eosin (H&E) staining, while qPCR was used to examine gene expression. PAT adipocytes were significantly smaller than those from VAT and had a more beige-like appearance in both LZR and OZR. In the OZR group, VAT adipocyte cell size increased significantly compared with LZR, while PAT showed no difference. Exercise and stress resulted in a significant reduction in VAT cellularity in OZR, while PAT showed no change. This suggests that PAT cellularity does not remodel significantly compared with VAT. These data indicate that the extracellular matrix of PAT is able to remodel more readily than in VAT. In the LZR group, exercise increased insulin receptor substrate 1 (IRS1) in PAT but was decreased in the OZR group. In VAT, exercise decreased IRS1 in LZR, while increasing it in OZR. This suggests that in obesity, VAT is more responsive to exercise and subsequently becomes less insulin resistant compared with PAT. Stress increased PPAR-γ expression in the VAT but decreased it in the PAT in the OZR group. This suggests that in obesity, stress increases adipogenesis more significantly in the VAT compared with PAT. To understand the role of leptin signaling in adipose tissue remodeling mechanistically, JAK2 autophosphorylation was inhibited using 5 µM 1,2,3,4,5,6-hexabromocyclohexane (Hex) in cultured 3T3-derived adipocytes. Palmitate treatment was used to induce cellular hypertrophy. Hex blocked adipocyte hypertrophy in response to palmitate treatment but not the increase in lipid droplet size. These data suggest that leptin signaling is necessary for adipocyte cell remodeling, and its absence induces whitening. Taken together, our data suggest that leptin signaling is necessary for adipocyte remodeling in response to obesity, exercise, and psychosocial stress.


Assuntos
Tecido Adiposo , Leptina , Masculino , Ratos , Animais , Ratos Zucker , Pericárdio , Palmitatos , Estresse Psicológico , Hipertrofia , Obesidade
2.
J Physiol ; 602(17): 4271-4289, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39106241

RESUMO

Studies have shown cerebrovascular dysfunction in offspring with full-gestational electronic cigarette (Ecig) exposure, but little is known about how individual trimester exposure impacts offspring health. This study aimed to determine if there is a critical window during gestation that contributes to vascular and anxiety-like behavioural changes seen with full-term exposure. To test this, rats were time-mated, and the pregnant dams were randomly assigned to Ecig exposure during first trimester (gestational day, GD2-7), second trimester (GD8-14), third trimester (GD15-21) or full-term gestation (GD2-21). We also assessed the effect of maternal preconception exposure. Both male and female offspring from all maternal exposure conditions were compared to offspring from dams under ambient air (control) conditions. Ecig exposure consisted of 60-puffs/day (5 days/week) using either 5 or 30 watts for each respective exposure group. We found that maternal exposure to Ecig in the second and third trimesters resulted in a decrease (23-38%) in vascular reactivity of the middle cerebral artery (MCA) reactivity in 3- and 6-month-old offspring compared to Air offspring. Further, the severity of impairment was comparable to the full-term exposure (31-46%). Offspring also displayed changes in body composition, body mass, anxiety-like behaviour and locomotor activity, indicating that Ecigs influence neurodevelopment and metabolism. Maternal preconception exposure showed no impact on offspring body mass, anxiety-like behaviour, or vascular function. Thus, the critical exposure window where Ecig affects vascular development in offspring occurs during mid- to late-gestation in pregnancy, and both 5 W and 30 W exposure produce significant vascular dysfunction compared to Air. KEY POINTS: Exposure to electronic cigarettes (Ecigs) is known to increase risk factors for cardiovascular disease in both animals and humans. Maternal Ecig use during pregnancy in rodents is found to impair the vascular health of adolescent and adult offspring, but the critical gestation window for Ecig-induced vascular impairment is not known. This study demonstrates Ecig exposure during mid- and late-gestation (i.e. second or third trimester) results in impaired endothelial cell-mediated dilatation (i.e. middle cerebral artery reactivity) and alters anxiety-like behaviour in offspring. Maternal exposure prior to conception did not impact offspring's vascular or anxiety-like behavioural outcomes. Rodent models have been a reliable and useful predictor of inhalation-induced harm to humans. These data indicate maternal use of Ecigs during pregnancy should not be considered safe, and begin to inform clinicians and women about potential long-term harm to their offspring.


Assuntos
Sistemas Eletrônicos de Liberação de Nicotina , Efeitos Tardios da Exposição Pré-Natal , Ratos Sprague-Dawley , Animais , Feminino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Masculino , Ratos , Ansiedade , Artéria Cerebral Média/efeitos dos fármacos , Exposição Materna/efeitos adversos
3.
Am J Physiol Heart Circ Physiol ; 327(2): H509-H517, 2024 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-38874616

RESUMO

Aging is associated with a significant decline in aerobic capacity assessed by maximal exercise oxygen consumption (V̇o2max). The relative contributions of the specific V̇o2 components driving this decline, namely cardiac output (CO) and arteriovenous oxygen difference (A - V)O2, remain unclear. We examined this issue by analyzing data from 99 community-dwelling participants (baseline age: 21-96 yr old; average follow-up: 12.6 yr old) from the Baltimore Longitudinal Study of Aging, free of clinical cardiovascular disease. V̇o2peak, a surrogate of V̇o2max, was used to assess aerobic capacity during upright cycle ergometry. Peak exercise left ventricular volumes, heart rate, and CO were estimated using repeated gated cardiac blood pool scans. The Fick equation was used to calculate (A - V)O2diff,peak from COpeak and V̇o2peak. In unadjusted models, V̇o2peak, (A - V)O2diff,peak, and COpeak declined longitudinally over time at steady rates with advancing age. In multiple linear regression models adjusting for baseline values and peak workload, however, steeper declines in V̇o2peak and (A - V)O2diff,peak were observed with advanced entry age but not in COpeak. The association between the declines in V̇o2peak and (A - V)O2diff,peak was stronger among those ≥50 yr old compared with their younger counterparts, but the difference between the two age groups did not reach statistical significance. These findings suggest that age-associated impairment of peripheral oxygen utilization during maximal exercise poses a stronger limitation on peak V̇o2 than that of CO. Future studies examining interventions targeting the structure and function of peripheral muscles and their vasculature to mitigate age-associated declines in (A - V)O2diff are warranted.NEW & NOTEWORTHY The age-associated decline in aerobic exercise performance over an average of 13 yr in community-dwelling healthy individuals is more closely associated with decreased peripheral oxygen utilization rather than decreased cardiac output. This association was more evident in older than younger individuals. These findings suggest that future studies with larger samples examine whether these associations vary across the age range and whether the decline in cardiac output plays a greater role earlier in life. In addition, studies focused on determinants of peripheral oxygen uptake by exercising muscle may guide the selection of preventive strategies designed to maintain physical fitness with advancing age.


Assuntos
Envelhecimento , Débito Cardíaco , Consumo de Oxigênio , Humanos , Idoso , Pessoa de Meia-Idade , Masculino , Consumo de Oxigênio/fisiologia , Feminino , Adulto , Envelhecimento/fisiologia , Envelhecimento/metabolismo , Estudos Longitudinais , Idoso de 80 Anos ou mais , Adulto Jovem , Baltimore , Fatores Etários , Tolerância ao Exercício , Teste de Esforço
4.
Toxicol Appl Pharmacol ; 474: 116631, 2023 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-37468077

RESUMO

Electronic cigarettes (e-cigs) are customizable tobacco products that allow users to select e-liquid composition, flavors, and (in some devices) adjust wattage or heat used to generate e-cig aerosol. This study compared vascular outcomes in a conducting vessel (thoracic aorta) and a resistance artery (middle cerebral artery, MCA) in C57Bl/6 mice exposed to e-cig aerosol generated from either pure vegetable glycerin (VG) or pure propylene glycol (PG) over 60-min (Study 1), and separately the effect of using 5- vs. 30-watt settings with an exposure of 100-min (Study 2). In Study 1, aortic endothelial-dependent-dilation (EDD) was only impaired with PG- exposure (p < 0.05) compared with air. In the MCA, EDD response was impaired by ∼50% in both VG and PG groups compared with air (p < 0.05). In Study 2, the aortic EDD responses were not different for either 5- or 30-watt exposed groups compared with air controls; however, in the MCA, both 5- and 30-watt groups were impaired by 32% and 55%, respectively, compared with air controls (p < 0.05). These pre-clinical data provide evidence that chronic exposure to aerosol produced by either VG or PG, and regardless of the wattage used, leads to vascular dysfunction at multiple levels within the arterial system. For all exposures, we observed greater impairment of arterial reactivity in a resistance artery (i.e. MCA) compared with the aorta. These data could suggest the smaller arteries may be more sensitive or first to be affected, or that different mechanism(s) for impairment may be involved depending on arterial hierarchy.


Assuntos
Sistemas Eletrônicos de Liberação de Nicotina , Vaping , Animais , Camundongos , Propilenoglicol/toxicidade , Vaping/efeitos adversos , Glicerol/toxicidade , Aerossóis
5.
Am J Physiol Heart Circ Physiol ; 323(3): H475-H489, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35904886

RESUMO

The study of peripheral vasculopathy with chronic metabolic disease is challenged by divergent contributions from spatial (the level of resolution or specific tissue being studied) and temporal origins (evolution of the developing impairments in time). Over many years of studying the development of skeletal muscle vasculopathy and its functional implications, we may be at the point of presenting an integrated conceptual model that addresses these challenges within the obese Zucker rat (OZR) model. At the early stages of metabolic disease, where systemic markers of elevated cardiovascular disease risk are present, the only evidence of vascular dysfunction is at postcapillary and collecting venules, where leukocyte adhesion/rolling is elevated with impaired venular endothelial function. As metabolic disease severity and duration increases, reduced microvessel density becomes evident as well as increased variability in microvascular hematocrit. Subsequently, hemodynamic impairments to distal arteriolar networks emerge, manifesting as increasing perfusion heterogeneity and impaired arteriolar reactivity. This retrograde "wave of dysfunction" continues, creating a condition wherein deficiencies to the distal arteriolar, capillary, and venular microcirculation stabilize and impairments to proximal arteriolar reactivity, wall mechanics, and perfusion distribution evolve. This proximal arteriolar dysfunction parallels increasing failure in fatigue resistance, hyperemic responses, and O2 uptake within self-perfused skeletal muscle. Taken together, these results present a conceptual model for the retrograde development of peripheral vasculopathy with chronic metabolic disease and provide insight into the timing and targeting of interventional strategies to improve health outcomes.NEW & NOTEWORTHY Working from an established database spanning multiple scales and times, we studied progression of peripheral microvascular dysfunction in chronic metabolic disease. The data implicate the postcapillary venular endothelium as the initiating site for vasculopathy. Indicators of dysfunction, spanning network structures, hemodynamics, vascular reactivity, and perfusion progress in an insidious retrograde manner to present as functional impairments to muscle blood flow and performance much later. The silent vasculopathy progression may provide insight into clinical treatment challenges.


Assuntos
Doenças Metabólicas , Síndrome Metabólica , Doenças Vasculares Periféricas , Animais , Síndrome Metabólica/metabolismo , Microcirculação/fisiologia , Músculo Esquelético/irrigação sanguínea , Obesidade/complicações , Ratos , Ratos Zucker
6.
Exp Physiol ; 107(8): 994-1006, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35661445

RESUMO

NEW FINDINGS: What is the central question of this study? Acute exposure to electronic cigarettes (Ecigs) triggers abnormal vascular responses in systemic arteries; however, effects on cerebral vessels are poorly understood and time for recovery is not known. We hypothesized that exposure to cigarettes or Ecigs would trigger rapid (<4 h) impairment of the middle cerebral artery (MCA) but that this would resolve by 24 h. What is the main finding and its importance? Cigarettes and Ecigs caused similar degree and duration of MCA impairment. We find it takes ~72 hours after exposure for MCA function to return to normal. This suggests that Ecig use is likely to produce similar adverse vascular health outcomes to those seen with cigarette smoke. ABSTRACT: Temporal influences of electronic cigarettes (Ecigs) on blood vessels are poorly understood. In this study, we evaluated a single episode of cigarette versus Ecig exposure on middle cerebral artery (MCA) reactivity and determined how long after the exposure MCA responses took to return to normal. We hypothesized that cigarette and Ecig exposure would induce rapid (<4 h) reduction in MCA endothelial function and would resolve within 24 h. Sprague-Dawley rats (4 months old) were exposed to either air (n = 5), traditional cigarettes (20 puffs, n = 16) or Ecigs (20-puff group, n = 16; or 60-puff group, n = 12). Thereafter, the cigarette and Ecig groups were randomly assigned for postexposure vessel myography testing on day 0 (D0, 1-4 h postexposure), day 1 (D1, 24-28 h postexposure), day 2 (D2, 48-52 h postexposure) and day 3 (72-76 h postexposure). The greatest effect on endothelium-dependent dilatation was observed within 24 h of exposure (∼50% decline between D0 and D1) for both cigarette and Ecig groups, and impairment persisted with all groups for up to 3 days. Changes in endothelium-independent dilatation responses were less severe (∼27%) and shorter lived (recovering by D2) compared with endothelium-dependent dilatation responses. Vasoconstriction in response to serotonin (5-HT) was similar to endothelium-independent dilatation, with greatest impairment (∼45% for all exposure groups) at D0-D1, returning to normal by D2. These data show that exposure to cigarettes and Ecigs triggers a similar level/duration of cerebrovascular dysfunction after a single exposure. The finding that Ecig (without nicotine) and cigarette (with nicotine) exposure produce the same effects suggesting that nicotine is not likely to be triggering MCA dysfunction, and that vaping (with/without nicotine) has potential to produce the same vascular harm and/or disease as smoking.


Assuntos
Transtornos Cerebrovasculares , Sistemas Eletrônicos de Liberação de Nicotina , Animais , Transtornos Cerebrovasculares/induzido quimicamente , Nicotina/efeitos adversos , Ratos , Ratos Sprague-Dawley , Vaping/efeitos adversos
7.
J Vasc Res ; 58(5): 286-300, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33971663

RESUMO

The obese Zucker rat (OZR) manifests multiple risk factors for impaired cerebrovascular function, including hypertension and insulin resistance although how they combine to produce integrated vascular function is unclear. As studies have suggested that myogenic activation (MA) severity for middle cerebral arteries (MCAs) may be proportional to hypertension severity, we hypothesized that MA will negatively correlate with dilator reactivity in OZR. MA of MCA from OZR was divided into low, medium, and high based on the slope of MA, while MCA reactivity and vascular metabolite bioavailability were assessed in all groups. Endothelium-dependent dilation of MCA in OZR was attenuated and correlated with the MA slope. Treatment of OZR MCA with TEMPOL (antioxidant) improved dilation in low or medium MA groups, but had less impact on high MA. Alternatively, treatment with gadolinium to normalize MA in OZR had reduced impact on dilator reactivity in MCA from low and medium MA groups, but improved responses in the high group. Treatment with both agents resulted in dilator responses that were comparable across all groups. These results suggest that, under conditions with stronger MA, endothelial function may receive some protection despite the environment, potentially from the ability of MCA to reduce wall tension despite increased pressure.


Assuntos
Circulação Cerebrovascular , Endotélio Vascular/fisiopatologia , Síndrome Metabólica/fisiopatologia , Artéria Cerebral Média/fisiopatologia , Músculo Liso Vascular/fisiopatologia , Resistência Vascular , Vasodilatação , Animais , Antioxidantes/farmacologia , Circulação Cerebrovascular/efeitos dos fármacos , Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Masculino , Síndrome Metabólica/metabolismo , Artéria Cerebral Média/efeitos dos fármacos , Artéria Cerebral Média/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Ratos Zucker , Resistência Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia
8.
Chem Senses ; 462021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34718440

RESUMO

The T1R and T2R families of G protein-coupled receptors (GPCRs) initiate tastant perception by signaling via guanine nucleotide exchange and hydrolysis performed by associated heterotrimeric G proteins (Gαßγ). Heterotrimeric G protein signal termination is sped up by Gα-directed GTPase-accelerating proteins (GAPs) known as the Regulators of G protein Signaling (RGS proteins). Of this family, RGS21 is highly expressed in lingual epithelial cells and we have shown it acting in vitro to decrease the potency of bitterants on cultured cells. However, constitutive RGS21 loss in mice reduces organismal response to GPCR-mediated tastants-opposite to expectations arising from observed in vitro activity of RGS21 as a GAP and inhibitor of T2R signaling. Here, we show reduced quinine aversion and reduced sucrose preference by mice lacking RGS21 does not result from post-ingestive effects, as taste-salient brief-access tests confirm the reduced bitterant aversion and reduced sweetener preference seen using two-bottle choice testing. Eliminating Rgs21 expression after chemosensory system development, via tamoxifen-induced Cre recombination in eight week-old mice, led to a reduction in quinine aversive behavior that advanced over time, suggesting that RGS21 functions as a negative regulator to sustain stable bitter tastant reception. Consistent with this notion, we observed downregulation of multiple T2R proteins in the lingual tissue of Rgs21-deficient mice. Reduced tastant-mediated responses exhibited by mice lacking Rgs21 expression either since birth or in adulthood has highlighted the potential requirement for a GPCR GAP to maintain the full character of tastant signaling, likely at the level of mitigating receptor downregulation.


Assuntos
Proteínas RGS , Animais , Proteínas de Ligação ao GTP , Camundongos , Proteínas RGS/genética , Proteínas RGS/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais , Paladar
9.
Exp Physiol ; 106(6): 1343-1358, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33913209

RESUMO

NEW FINDINGS: What is the central question of this study? Thoracic perivascular adipose tissue (tPVAT) is known to, in part, regulate aortic function: what are the effects of unpredictable chronic mild stress (UCMS) on the tPVAT regulation of aortic function and what is the role of exercise training in alleviating the potential negative actions of UCMS on tPVAT? What is the main finding and its importance? UCMS causes tPVAT to disrupt endothelium-dependent dilatation, increases inflammatory cytokine production and diminishes tPVAT-adiponectin. Exercise training proved efficacious in preventing tPVAT-mediated disruption of aortic function. The data support a tPVAT mechanism through which chronic stress negatively impacts vascular health, which adds to our knowledge of how psychological disorders might increase the risk of cardiovascular disease. ABSTRACT: Chronic stress is a major risk for cardiovascular disease. Perivascular adipose tissue (PVAT) has been shown to regulate vascular function; however, the impact of chronic stress and the comorbidity of metabolic syndrome (MetS) on thoracic (t)PVAT is unknown. Additionally, aerobic exercise training (AET) is known to combat the pathology of MetS and chronic stress, but the role of tPVAT in these actions is also unknown. Therefore, the purpose of this study was to examine the effects of unpredictable chronic mild stress (UCMS) on the tPVAT regulation of aortic function and the preventative effect of AET. Lean (LZR) and obese (OZR) Zucker rats (16-17 weeks old) were exposed to 8 weeks of UCMS with and without treadmill exercise (AET). In LZR, UCMS impaired aortic endothelium-dependent dilatation (EDD) (assessed ex vivo by wire myography) and aortic stiffness (assessed by elastic modulus) with no change in OZR subject to UCMS. However, both LZR and OZR UCMS tPVAT impaired EDD compared to respective controls. LZR and OZR subject to UCMS had higher oxidative stress production, diminished adiponectin and impaired aortic nitric oxide levels. Divergently, UCMS induced greater inflammatory cytokine production in LZR UCMS tPVAT, but not in OZR UCMS tPVAT. AET prevented the tPVAT impairment of aortic relaxation with UCMS in LZR and OZR. Additionally, AET reduced aortic stiffness in both LZR and OZR. These beneficial effects on tPVAT regulation of the aorta are likely due to AET preservation of adiponectin, reduced oxidative stress and inflammation, and enhanced nitric oxide. UCMS impaired tPVAT-regulated aortic function in LZR, and augmented MetS-induced EDD in OZR. Conversely, AET in combination with UCMS largely preserved aortic function and the tPVAT environment, in both groups.


Assuntos
Síndrome Metabólica , Tecido Adiposo/metabolismo , Animais , Aorta/metabolismo , Obesidade/metabolismo , Ratos , Ratos Zucker
10.
Exerc Sport Sci Rev ; 49(3): 188-196, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33831902

RESUMO

Adipose tissue and arterial dysfunction are common in the obese state. Perivascular adipose tissue (PVAT) plays an important role in mediating arterial health, and with obesity, the PVAT dysfunction negatively affects arterial health. Exercise training exerts direct and beneficial effects on PVAT, providing an additional and novel pathway by which exercise can improve arterial health in diseased populations.


Assuntos
Tecido Adiposo , Obesidade , Artérias , Exercício Físico , Humanos , Transdução de Sinais
11.
Physiol Genomics ; 50(10): 876-883, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30029587

RESUMO

Increasing evidence suggests that there are innate differences between sexes with respect to stroke pathophysiology; however, the molecular mechanisms underlying these differences remain unclear. In this investigation, we employed a shotgun approach to broadly profile sex-associated differences in the plasma proteomes of a small group of male ( n = 6) and female ( n = 4) ischemic stroke patients. Peripheral blood was sampled during the acute phase of care, and liquid chromatography electrospray ionization mass spectrometry was used to quantify plasma proteins. We observed widespread differences in plasma composition, as 77 out of 294 detected proteins were significantly differentially expressed between sexes. Corticosteroid-binding globulin (CBG), a negative acute-phase reactant that inversely regulates levels of bioactive free cortisol, was the most dramatically differentially regulated, exhibiting 16-fold higher abundance in plasma from women relative to men. Furthermore, functional annotation analysis revealed that the remaining differentially expressed proteins were significantly enriched for those involved in response to corticosteroid signaling. Plasma CBG levels were further examined in an additional group of male ( n = 19) and female ( n = 28) ischemic stroke patients, as well as a group of male ( n = 13) and female ( n = 18) neurologically normal controls. CBG levels were significantly reduced in male stroke patients relative to male controls; however, no differences were observed between female stroke patients and female controls, suggesting that women may exhibit an attenuated cortisol response to stroke. Collectively, our findings reinforce the idea that there are sex-associated differences in stroke pathophysiology and suggest that cortisol signaling should be investigated further as a potential molecular mediator.


Assuntos
Corticosteroides/metabolismo , Isquemia Encefálica/metabolismo , Proteoma/metabolismo , Proteômica/métodos , Acidente Vascular Cerebral/metabolismo , Corticosteroides/sangue , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/complicações , Estudos de Coortes , Feminino , Humanos , Hidrocortisona/sangue , Hidrocortisona/metabolismo , Masculino , Fatores Sexuais , Transdução de Sinais , Acidente Vascular Cerebral/etiologia , Transcortina/metabolismo
12.
Am J Physiol Heart Circ Physiol ; 314(5): H1085-H1097, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29451819

RESUMO

While it is known that chronic stress and clinical depression are powerful predictors of poor cardiovascular outcomes, recent clinical evidence has identified correlations between the development of metabolic disease and depressive symptoms, creating a combined condition of severely elevated cardiovascular disease risk. In this study, we used the obese Zucker rat (OZRs) and the unpredictable chronic mild stress (UCMS) model to determine the impact of preexisting metabolic disease on the relationship between chronic stress/depressive symptoms and vascular function. Additionally, we determined the impact of metabolic syndrome on sex-based protection from chronic stress/depressive effects on vascular function in female lean Zucker rats (LZRs). In general, vasodilator reactivity was attenuated under control conditions in OZRs compared with LZRs. Although still impaired, conduit arterial and resistance arteriolar dilator reactivity under control conditions in female OZRs was superior to that in male or ovariectomized (OVX) female OZRs, largely because of better maintenance of vascular nitric oxide and prostacyclin levels. However, imposition of metabolic syndrome in combination with UCMS in OZRs further impaired dilator reactivity in both vessel subtypes to a similarly severe extent and abolished any protective effect in female rats compared with male or OVX female rats. The loss of vascular protection in female OZRs with UCMS was reflected in vasodilator metabolite levels, which closely matched those in male and OVX female OZRs subjected to UCMS. These results suggest that presentation of metabolic disease in combination with depressive symptoms can overwhelm the vasoprotection identified in female rats and, thereby, may reflect a severe impairment to normal endothelial function. NEW & NOTEWORTHY This study addresses the protection from chronic stress- and depression-induced vascular dysfunction identified in female compared with male or ovariectomized female rats. We determined the impact of preexisting metabolic disease, a frequent comorbidity of clinical depression in humans, on that vascular protection. With preexisting metabolic syndrome, female rats lost all protection from chronic stress/depressive symptoms and became phenotypically similar to male and ovariectomized female rats, with comparably poor vasoactive dilator metabolite profiles.


Assuntos
Aorta Torácica/fisiopatologia , Doenças Cardiovasculares/prevenção & controle , Depressão/fisiopatologia , Síndrome Metabólica/fisiopatologia , Artéria Cerebral Média/fisiopatologia , Estresse Psicológico/fisiopatologia , Vasodilatação , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Comportamento Animal , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Doenças Cardiovasculares/psicologia , Doença Crônica , Depressão/metabolismo , Depressão/psicologia , Modelos Animais de Doenças , Feminino , Hormônios Esteroides Gonadais/metabolismo , Masculino , Síndrome Metabólica/metabolismo , Artéria Cerebral Média/efeitos dos fármacos , Artéria Cerebral Média/metabolismo , Ovariectomia , Estresse Oxidativo , Fatores de Proteção , Ratos Zucker , Fatores Sexuais , Estresse Psicológico/metabolismo , Estresse Psicológico/psicologia , Vasoconstrição , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia
13.
Am J Physiol Heart Circ Physiol ; 314(5): H1070-H1084, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29451821

RESUMO

The increasing prevalence and severity of clinical depression are strongly correlated with vascular disease risk, creating a comorbid condition with poor outcomes but demonstrating a sexual disparity whereby female subjects are at lower risk than male subjects for subsequent cardiovascular events. To determine the potential mechanisms responsible for this protection against stress/depression-induced vasculopathy in female subjects, we exposed male, intact female, and ovariectomized (OVX) female lean Zucker rats to the unpredictable chronic mild stress (UCMS) model for 8 wk and determined depressive symptom severity, vascular reactivity in ex vivo aortic rings and middle cerebral arteries (MCA), and the profile of major metabolites regulating vascular tone. While all groups exhibited severe depressive behaviors from UCMS, severity was significantly greater in female rats than male or OVX female rats. In all groups, endothelium-dependent dilation was depressed in aortic rings and MCAs, although myogenic activation and vascular (MCA) stiffness were not impacted. Higher-resolution results from pharmacological and biochemical assays suggested that vasoactive metabolite profiles were better maintained in female rats with normal gonadal sex steroids than male or OVX female rats, despite increased depressive symptom severity (i.e., higher nitric oxide and prostacyclin and lower H2O2 and thromboxane A2 levels). These results suggest that female rats exhibit more severe depressive behaviors with UCMS but are partially protected from the vasculopathy that afflicts male rats and female rats lacking normal sex hormone profiles. Determining how female sex hormones afford partial vascular protection from chronic stress and depression is a necessary step for addressing the burden of these conditions on cardiovascular health. NEW & NOTEWORTHY This study used a translationally relevant model for chronic stress and elevated depressive symptoms to determine how these factors impact conduit and resistance arteriolar function in otherwise healthy rats. While chronic stress leads to an impaired vascular reactivity associated with elevated oxidant stress, inflammation, and reduced metabolite levels, we demonstrated partial protection from vascular dysfunction in female rats with normal sex hormone profiles compared with male or ovariectomized female rats.


Assuntos
Aorta Torácica/fisiopatologia , Doenças Cardiovasculares/prevenção & controle , Depressão/fisiopatologia , Artéria Cerebral Média/fisiopatologia , Estresse Psicológico/fisiopatologia , Vasodilatação , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Comportamento Animal , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Doenças Cardiovasculares/psicologia , Doença Crônica , Depressão/metabolismo , Depressão/psicologia , Modelos Animais de Doenças , Feminino , Hormônios Esteroides Gonadais/metabolismo , Masculino , Artéria Cerebral Média/efeitos dos fármacos , Artéria Cerebral Média/metabolismo , Ovariectomia , Estresse Oxidativo , Fatores de Proteção , Ratos Zucker , Fatores Sexuais , Estresse Psicológico/metabolismo , Estresse Psicológico/psicologia , Vasoconstrição , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia
14.
Exp Physiol ; 103(4): 590-603, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29349831

RESUMO

NEW FINDINGS: What is the central question of this study? Tumour necrosis factor-α (TNFα) has been shown to impair vascular function, but the impact of thoracic aorta perivascular adipose tissue (tPVAT)-derived TNFα on tPVAT and aortic function in metabolic syndrome is unknown. What is the main finding and its importance? Release of TNFα by tPVAT causes production of reactive oxygen species in tPVAT through activation of an NADPH-oxidase 2 (NOX2)-dependent pathway, activates production of aortic reactive oxygen species and mediates aortic stiffness, potentially through matrix metalloproteinase 9 activity. Neutralization of TNFα and/or inhibition of NOX2 blocks the tPVAT-induced impairment of aortic function. These data partly implicate tPVAT NOX2 and TNFα in mediating the vascular pathology of metabolic syndrome. ABSTRACT: Perivascular adipose tissue (PVAT) is recognized for its vasoactive effects, but it is unclear how metabolic syndrome impacts thoracic aorta (t)PVAT and the subsequent effect on functional and structural aortic stiffness. Thoracic aorta and tPVAT were removed from 16- to 17-week-old lean (LZR, n = 16) and obese Zucker rats (OZR, n = 16). The OZR presented with aortic endothelial dysfunction, assessed by wire myography, and increased aortic stiffness, assessed by elastic modulus. The OZR tPVAT exudate further exacerbated the endothelial dysfunction, reducing nitric oxide and endothelium-dependent relaxation (P < 0.05). Additionally, OZR tPVAT exudate had increased MMP9 activity (P < 0.05) and further increased the elastic modulus of the aorta after 72 h of co-culture (P < 0.05). We found that the observed aortic dysfunction caused by OZR tPVAT was mediated through increased production and release of tumour necrosis factor-α (TNFα; P < 0.01), which was dependent on tPVAT NADPH-oxidase 2 (NOX2) activity. The OZR tPVAT release of reactive oxygen species and subsequent aortic dysfunction were inhibited by TNFα neutralization and/or inhibition of NOX2. Additionally, we found that OZR tPVAT had reduced activity of the active sites of the 20S proteasome (P < 0.05) and reduced superoxide dismutase activity (P < 0.01). In conclusion, metabolic syndrome causes tPVAT dysfunction through an interplay between TNFα and NOX2 that leads to tPVAT-mediated aortic stiffness by activation of aortic reactive oxygen species and increased MMP9 activity.


Assuntos
Tecido Adiposo/metabolismo , Tecido Adiposo/fisiopatologia , Aorta/metabolismo , Aorta/fisiopatologia , Síndrome Metabólica/fisiopatologia , NADPH Oxidase 2/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Síndrome Metabólica/metabolismo , Óxido Nítrico/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Ratos , Ratos Zucker , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/fisiologia
15.
Exp Physiol ; 103(5): 761-776, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29436736

RESUMO

NEW FINDINGS: What is the central question of this study? How does chronic stress impact cerebrovascular function and does metabolic syndrome accelerate the cerebrovascular adaptations to stress? What role does exercise training have in preventing cerebrovascular changes to stress and metabolic syndrome? What is the main finding and its importance? Stressful conditions lead to pathological adaptations of the cerebrovasculature via an oxidative nitric oxide pathway, and the presence of metabolic syndrome produces a greater susceptibility to stress-induced cerebrovascular dysfunction. The results also provide insight into the mechanisms that may contribute to the influence of stress and the role of exercise in preventing the negative actions of stress on cerebrovascular function and structure. ABSTRACT: Chronic unresolvable stress leads to the development of depression and cardiovascular disease. There is a high prevalence of depression with the metabolic syndrome (MetS), but to what extent the MetS concurrent with psychological stress affects cerebrovascular function is unknown. We investigated the differential effect of MetS on cerebrovascular structure/function in rats (16-17 weeks old) following 8 weeks of unpredictable chronic mild stress (UCMS) and whether exercise training could limit any cerebrovascular dysfunction. In healthy lean Zucker rats (LZR), UCMS decreased (28%, P < 0.05) ex vivo middle cerebral artery (MCA) endothelium-dependent dilatation (EDD), but changes in MCA remodelling and stiffness were not evident, though cerebral microvessel density (MVD) decreased (30%, P < 0.05). The presence of UCMS and MetS (obese Zucker rats; OZR) decreased MCA EDD (35%, P < 0.05) and dilatation to sodium nitroprusside (20%, P < 0.05), while MCA stiffness increased and cerebral MVD decreased (31%, P < 0.05), which were linked to reduced nitric oxide and increased oxidative levels. Aerobic exercise prevented UCMS impairments in MCA function and MVD in LZR, and partly restored MCA function, stiffness and MVD in OZR. Our data suggest that the benefits of exercise with UCMS were due to a reduction in oxidative stress and increased production of nitric oxide in the cerebral vessels. In conclusion, UCMS significantly impaired MCA structure and function, but the effects of UCMS were more substantial in OZR vs. LZR. Importantly, aerobic exercise when combined with UCMS prevented the MCA dysfunction through subtle shifts in nitric oxide and oxidative stress in the cerebral microvasculature.


Assuntos
Doenças Cardiovasculares/fisiopatologia , Síndrome Metabólica/fisiopatologia , Condicionamento Físico Animal/fisiologia , Estresse Psicológico/fisiopatologia , Animais , Depressão/fisiopatologia , Endotélio Vascular/fisiopatologia , Masculino , Artéria Cerebral Média/fisiopatologia , Óxido Nítrico/metabolismo , Estresse Oxidativo/fisiologia , Ratos , Ratos Zucker , Vasodilatação/fisiologia
16.
Microcirculation ; 24(2)2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28036148

RESUMO

PURPOSE: Although studies suggest elevated adrenergic activity paralleling metabolic syndrome in OZRs, the moderate hypertension and modest impact on organ perfusion question the multi-scale validity of these data. METHODS: To understand how adrenergic function contributes to vascular reactivity in OZR, we utilized a multi-scale approach to investigate pressure responses, skeletal muscle blood flow, and vascular reactivity following adrenergic challenge. RESULTS: For OZR, adrenergic challenge resulted in increased pressor responses vs LZRs, mediated via α1 receptors, with minimal contribution by either ROS or NO bioavailability. In situ gastrocnemius muscle of OZR exhibited blunted functional hyperemia, partially restored with α1 inhibition, although improved muscle performance and VO2 required combined treatment with TEMPOL. Within OZR in situ cremaster muscle, proximal arterioles exhibited a more heterogeneous constriction to adrenergic challenge, biased toward hyperresponsiveness, vs LZR. This increasingly heterogeneous pattern was mirrored in ex vivo arterioles, mediated via α1 receptors, with roles for ROS and NO bioavailability evident in hyperresponsive vessels only. CONCLUSIONS: These results support the central role of the α1 adrenoreceptor for augmented pressor responses and elevations in vascular resistance, but identify an increased heterogeneity of constrictor reactivity in OZR that is presently of unclear purpose.


Assuntos
Adrenérgicos/farmacologia , Síndrome Metabólica/fisiopatologia , Músculo Esquelético/irrigação sanguínea , Vasoconstrição/efeitos dos fármacos , Animais , Hemodinâmica/fisiologia , Perfusão , Pressorreceptores/metabolismo , Pressorreceptores/fisiologia , Ratos , Ratos Zucker , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Adrenérgicos alfa 1/fisiologia , Fluxo Sanguíneo Regional/fisiologia
17.
Exp Physiol ; 102(10): 1321-1331, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28737253

RESUMO

NEW FINDINGS: What is the central question of this study? Does a stroke event influence aortic endothelial function; and what is the role of peripheral circulating leucocytes in stroke on the vascular reactivity of the aorta? What is the main finding and its importance? In vitro co-culture experiments demonstrated that aortic endothelium-dependent relaxation was impaired when rat aortic rings were co-cultured with leucocytes stimulated with serum from stroke patients. Impaired vascular reactivity was not observed in aortic rings without leucocytes stimulated with serum from stroke patients or age-matched control patients with or without leucocytes. These data suggest that leucocyte-dependent altered aortic endothelium-dependent relaxation with stroke and the systemic consequences of stroke on vascular inflammation may occur in the aorta. Post-stroke inflammation has been linked to poor stroke outcomes. The vascular endothelium senses and responds to circulating factors, in particular inflammatory cytokines. Although stroke-associated local cerebrovascular dysfunction is well reported, the effects of a stroke on conduit artery function are not fully understood. We tested the hypothesis that serum from stroke patients triggers leucocyte-dependent aortic endothelial dysfunction that is associated with elevated concentrations of cytokines. Total leucocytes were isolated from healthy individuals, and the cells were incubated in serum from control subjects or stroke patients for 6 h. The quantity of cytokines in media was determined using an immunoassay. Vascular reactivity was determined by the rat aortic rings that were co-cultured with or without leucocytes and stimulated with serum samples from control subjects or stroke patients. Endothelium-dependent dilatation was significantly impaired in aortic rings co-cultured with leucocytes plus serum from stroke patients (50 ± 30 versus 85 ± 13%, P < 0.05) versus serum from control subjects. In contrast, no difference was observed in aortic function stimulated with serum from control subjects or stroke patients without total leucocytes. Likewise, total leucocyte-derived cytokine concentrations were significantly increased in a time-dependent manner on stimulation with serum from stroke patients (P < 0.05). These observations support the concept that the increased response of leucocytes drives the development of stroke-associated vascular endothelial dysfunction. As such, pharmacologically targeting the source of inflammatory cytokines might alleviate stroke-associated peripheral vascular dysfunction.


Assuntos
Aorta/fisiologia , Leucócitos/fisiologia , Acidente Vascular Cerebral/fisiopatologia , Doenças Vasculares/fisiopatologia , Adulto , Animais , Aorta/metabolismo , Artérias/metabolismo , Artérias/fisiopatologia , Técnicas de Cocultura/métodos , Citocinas/metabolismo , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Feminino , Humanos , Inflamação/metabolismo , Inflamação/fisiopatologia , Leucócitos/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Acidente Vascular Cerebral/metabolismo , Doenças Vasculares/metabolismo , Vasodilatação/fisiologia , Adulto Jovem
18.
Brain Inj ; 31(10): 1369-1375, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28585898

RESUMO

OBJECTIVE: The objective of this work was to assess the ability of peripheral blood cell-free DNA (cfDNA) levels to identify ischaemic stroke early in the acute phase of care, as well as to examine the relationship between peripheral blood cfDNA levels and stroke-induced innate immune system activation. METHODS: Upon emergency department admission, peripheral blood samples were obtained from 43 patients experiencing acute ischaemic stroke and 20 patients identified as stroke mimics. Plasma cfDNA levels were measured using quantitative polymerase chain reaction (qPCR), infarct volume and NIH stroke scale (NIHSS) were used to assess injury severity, and peripheral blood neutrophil count was used as a measure of innate immune system status. RESULTS: Peripheral blood cfDNA levels were significantly elevated in patients suffering stroke relative to those diagnosed as stroke mimics, and could differentiate between groups with 86% (95% CI = 72-95%) sensitivity and 75% (95% CI = 51-91%) specificity. Furthermore, cfDNA levels displayed significant positive associations between both infarct volume and peripheral blood neutrophil count within the stroke group. CONCLUSIONS: These findings suggest that assessment of peripheral blood cfDNA levels may be useful for the identification of ischaemic stroke in the acute care setting, and provide associative evidence that cfDNA is a potential activator of the peripheral innate immune system in response to cerebral ischaemia.


Assuntos
Isquemia Encefálica/sangue , Ácidos Nucleicos Livres/sangue , Imunidade Inata/fisiologia , Acidente Vascular Cerebral/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/imunologia
19.
J Physiol ; 594(8): 2233-43, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-25384789

RESUMO

A major challenge facing public health is the increased incidence and prevalence of the metabolic syndrome, a clinical condition characterized by excess adiposity, impaired glycaemic control, dyslipidaemia and moderate hypertension. The greatest concern for this syndrome is the profound increase in risk for development of peripheral vascular disease (PVD) in afflicted persons. However, ongoing studies suggest that reductions in bulk blood flow to skeletal muscle may not be the primary contributor to the premature muscle fatigue that is a hallmark of PVD. Compelling evidence has been provided suggesting that an increasingly spatially heterogeneous and temporally stable distribution of blood flow at successive arteriolar bifurcations in metabolic syndrome creates an environment where a large number of the pre-capillary arterioles have low perfusion, low haematocrit, and are increasingly confined to this state, with limited ability to adapt perfusion in response to a challenged environment. Single pharmacological interventions are unable to significantly restore function owing to a divergence in their spatial effectiveness, although combined therapeutic approaches to correct adrenergic dysfunction, elevated oxidant stress and increased thromboxane A2 improve perfusion-based outcomes. Integrated, multi-target therapeutic interventions designed to restore healthy network function and flexibility may provide for superior outcomes in subjects with metabolic syndrome-associated PVD.


Assuntos
Síndrome Metabólica/complicações , Músculo Esquelético/irrigação sanguínea , Doenças Vasculares Periféricas/etiologia , Animais , Humanos , Microcirculação , Músculo Esquelético/metabolismo , Doenças Vasculares Periféricas/metabolismo , Doenças Vasculares Periféricas/fisiopatologia , Tromboxanos/metabolismo
20.
Am J Physiol Heart Circ Physiol ; 310(4): H488-504, 2016 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-26702145

RESUMO

To determine the impact of progressive elevations in peripheral vascular disease (PVD) risk on microvascular function, we utilized eight rat models spanning "healthy" to "high PVD risk" and used a multiscale approach to interrogate microvascular function and outcomes: healthy: Sprague-Dawley rats (SDR) and lean Zucker rats (LZR); mild risk: SDR on high-salt diet (HSD) and SDR on high-fructose diet (HFD); moderate risk: reduced renal mass-hypertensive rats (RRM) and spontaneously hypertensive rats (SHR); high risk: obese Zucker rats (OZR) and Dahl salt-sensitive rats (DSS). Vascular reactivity and biochemical analyses demonstrated that even mild elevations in PVD risk severely attenuated nitric oxide (NO) bioavailability and caused progressive shifts in arachidonic acid metabolism, increasing thromboxane A2 levels. With the introduction of hypertension, arteriolar myogenic activation and adrenergic constriction were increased. However, while functional hyperemia and fatigue resistance of in situ skeletal muscle were not impacted with mild or moderate PVD risk, blood oxygen handling suggested an increasingly heterogeneous perfusion within resting and contracting skeletal muscle. Analysis of in situ networks demonstrated an increasingly stable and heterogeneous distribution of perfusion at arteriolar bifurcations with elevated PVD risk, a phenomenon that was manifested first in the distal microcirculation and evolved proximally with increasing risk. The increased perfusion distribution heterogeneity and loss of flexibility throughout the microvascular network, the result of the combined effects on NO bioavailability, arachidonic acid metabolism, myogenic activation, and adrenergic constriction, may represent the most accurate predictor of the skeletal muscle microvasculopathy and poor health outcomes associated with chronic elevations in PVD risk.


Assuntos
Microcirculação , Músculo Esquelético/irrigação sanguínea , Doenças Vasculares Periféricas/fisiopatologia , Animais , Arteríolas/fisiopatologia , Frutose/farmacologia , Hipertensão Renal/fisiopatologia , Músculo Esquelético/fisiopatologia , Óxido Nítrico/metabolismo , Consumo de Oxigênio/fisiologia , Perfusão , Ratos , Ratos Endogâmicos Dahl , Ratos Endogâmicos SHR , Ratos Sprague-Dawley , Ratos Zucker , Medição de Risco , Sódio na Dieta/farmacologia , Tromboxano A2/metabolismo
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