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1.
Am J Physiol Heart Circ Physiol ; 320(4): H1712-H1723, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33666502

RESUMO

Uterine spiral artery remodeling (UAR) is essential for placental perfusion and fetal development. A defect in UAR underpins placental ischemia disorders, e.g., preeclampsia, that result in maternal systemic vascular endothelial dysfunction and hypertension. We have established a model of impaired UAR by prematurely elevating maternal serum estradiol levels during the first trimester of baboon pregnancy. However, it is unknown whether this experimental paradigm is associated with maternal vascular endothelial dysfunction. Therefore, in the present study baboons were administered estradiol on days 25-59 of gestation to suppress UAR and maternal vascular function determined on day 165 (term = 184 days) peripherally and in skeletal muscle, which accounts for over 40% of body mass and 25% of resting systemic vascular resistance. Maternal serum sFlt-1 levels were 2.5-fold higher (P < 0.05), and skeletal muscle arteriolar endothelial nitric oxide synthase (eNOS) protein expression and luminal area, and skeletal muscle capillary density were 30-50% lower (P < 0.05) in UAR suppressed baboons. Coinciding with these changes in eNOS expression, luminal area, and capillary density, maternal brachial artery flow-mediated dilation and volume flow were 70% and 55% lower (P < 0.05), respectively, and mean arterial blood pressure 29% higher (P < 0.01) in UAR defective baboons. In summary, maternal vascular function was disrupted in a baboon model of impaired UAR. These results highlight the translational impact of this primate model and relevance to adverse conditions of human pregnancy underpinned by improper uterine artery transformation.NEW & NOTEWORTHY Maternal vascular dysfunction is a hallmark of abnormal human pregnancy, particularly early-onset preeclampsia, elicited by impaired UAR. The present study makes the novel discovery that maternal systemic vascular dysfunction was induced in a baboon experimental model of impaired UAR. This study highlights the translational relevance of this nonhuman primate model to adverse conditions of human pregnancy underpinned by defective UAR.


Assuntos
Pressão Arterial , Artéria Braquial/fisiopatologia , Hipertensão Induzida pela Gravidez/fisiopatologia , Microvasos/fisiopatologia , Músculo Esquelético/irrigação sanguínea , Artéria Uterina/fisiopatologia , Remodelação Vascular , Vasodilatação , Animais , Artéria Braquial/metabolismo , Modelos Animais de Doenças , Estradiol/análogos & derivados , Feminino , Idade Gestacional , Hipertensão Induzida pela Gravidez/induzido quimicamente , Hipertensão Induzida pela Gravidez/metabolismo , Microvasos/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo , Papio anubis , Gravidez , Primeiro Trimestre da Gravidez , Artéria Uterina/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue
2.
PLoS One ; 16(2): e0246636, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33556081

RESUMO

BACKGROUND: Data on microcirculatory pattern of COVID-19 critically ill patients are scarce. The objective was to compare sublingual microcirculation parameters of critically ill patients according to the severity of the disease. METHODS: The study is a single-center prospective study with critically ill COVID-19 patients admitted in ICU. Sublingual microcirculation was assessed by IDF microscopy within 48 hours of ICU admission. Microcirculatory flow index (MFI), proportion of perfused vessel (PPV), total vessel density (TVD), De Backer score (DBS), perfused vessel density (PVD) and heterogeneity index (HI) were assessed. Patients were divided in 2 groups (severe and critical) according to the World health organization definition. FINDINGS: From 19th of March to 7th of April 2020, 43 patients were included. Fourteen patients (33%) were in the severe group and twenty-nine patients (67%) in the critical group. Patients in the critical group were all mechanically ventilated. The critical group had significantly higher values of MFI, DBS and PVD in comparison to severe group (respectively, PaCO2: 49 [44-45] vs 36 [33-37] mmHg; p<0,0001, MFI: 2.8 ± 0.2 vs 2.5 ± 0.3; p = 0.001, DBS: 12.7 ± 2.6 vs 10.8 ± 2.0 vessels mm-2; p = 0.033, PVD: 12.5 ± 3.0 vs 10.1 ± 2.4 mm.mm-2; p = 0.020). PPV, HI and TVD were similar between groups Correlation was found between microcirculatory parameters and PaCO2 levels. CONCLUSION: Critical COVID-19 patients under mechanical ventilation seem to have higher red blood cell velocity than severe non-ventilated patients.


Assuntos
/fisiopatologia , Estado Terminal , Microcirculação/fisiologia , Microvasos/fisiopatologia , Idoso , Dióxido de Carbono/metabolismo , Feminino , Hemodinâmica , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Oxigênio/metabolismo , Pressão Parcial , Estudos Prospectivos , /fisiologia
3.
Am J Physiol Heart Circ Physiol ; 320(4): H1393-H1402, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33481699

RESUMO

Preeclampsia is associated with adverse maternal health outcomes later in life. Vascular endothelial dysfunction has been previously described following preeclampsia. We hypothesized that microvascular endothelial dysfunction associated with preeclampsia persists postpartum and may identify those at greatest risk of future cardiovascular disease. The objective of this study was to examine postpartum microvascular endothelial function in women after a pregnancy complicated by preeclampsia. Women with previous preeclampsia (n = 30) and normotensive controls (n = 30) between 6 mo and 5 yr postpartum were recruited. Severity of preeclampsia [severe (n = 16) and mild (n = 14)] was determined by standardized chart review. Microvascular reactivity in the forearm was measured with laser speckle contrast imaging, coupled with iontophoresis; endothelium-dependent and endothelium-independent vasodilation was induced with 1% acetylcholine and sodium nitroprusside solutions, respectively. A postocclusive reactive hyperemia test assessed vasodilatory response following three minutes of suprasystolic (200 mmHg) occlusion with a mechanized cuff. Women with prior severe preeclampsia exhibited significantly higher vasodilation to acetylcholine and sodium nitroprusside compared to controls (P < 0.01; P = 0.03) and prior mild preeclampsia (P = 0.03; P < 0.01). Neither the degree of postocclusive reactive hyperemia (P = 0.98), nor time to return halfway to baseline [OR = 1.026 (0.612, 1.72); P = 0.92], differed between preeclampsia and controls. In conclusion, severe preeclampsia is associated with heightened postpartum microvascular endothelium-dependent and endothelium-independent vasoreactivity. These changes, or a common antecedent, may be linked to postpartum alterations in vascular function that predispose women to disease after preeclampsia. Further investigation should identify the contributing mechanism and the degree to which it could be amenable to medical intervention.NEW & NOTEWORTHY We examine maternal microvascular function after preeclampsia, identifying heightened endothelium-dependent and endothelium-independent microvascular reactivity following severe disease. Our study represents a noteworthy addition to the existing literature with the use of a novel imaging modality, vascular perturbation, postpartum time point, and patient population with differentiation of preeclampsia into severe and nonsevere subtypes. These results represent a novel addition to the growing clinical and academic understanding of maternal health outcomes following preeclampsia.


Assuntos
Endotélio Vascular/fisiopatologia , Antebraço/irrigação sanguínea , Microcirculação , Microvasos/fisiopatologia , Período Pós-Parto , Pré-Eclâmpsia/fisiopatologia , Vasodilatação , Administração Cutânea , Adulto , Estudos de Casos e Controles , Endotélio Vascular/efeitos dos fármacos , Feminino , Humanos , Iontoforese , Microcirculação/efeitos dos fármacos , Microvasos/efeitos dos fármacos , Pré-Eclâmpsia/diagnóstico , Gravidez , Índice de Gravidade de Doença , Vasodilatação/efeitos dos fármacos , Vasodilatadores/administração & dosagem
4.
Microvasc Res ; 133: 104078, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32980388

RESUMO

The present study assessed the impact of impaired tetrahydrobiopterin (BH4) production on vasoreactivity from conduit and small arteries along the vascular tree as seen during aging. For this purpose, the mutant hyperphenylalaninemic mouse (hph-1) was used. This model is reported to be deficient in GTP cyclohydrolase I, a rate limiting enzyme in BH4 biosynthesis. BH4 is a key regulator of vascular homeostasis by regulating the nitric oxide synthase 3 (NOS3) activity. In GTP-CH deficient mice, the aortic BH4 levels were decreased, by -77% in 12 week-middle-aged mice (young) and by -83% in 35-45 week-middle-aged mice (middle-aged). In young hph-1, the mesenteric artery ability to respond to flow was slightly reduced by 9%. Aging induced huge modification in many vascular functions. In middle-aged hph-1, we observed a decrease in aortic cGMP levels, biomarker of NO availability (-46%), in flow-mediated vasodilation of mesenteric artery (-31%), in coronary hyperemia response measured in isolated heart following transient ischemia (-27%) and in cutaneous microcirculation dilation in response to acetylcholine assessed in vivo by laser-doppler technic (-69%). In parallel, the endothelium-dependent relaxation in response to acetylcholine in conduit blood vessel, measured on isolated aorta rings, was unchanged in hph-1 mice whatever the age. Our findings demonstrate that in middle-aged GTP-CH depleted mice, the reduction of BH4 was characterized by an alteration of microcirculation dilatory properties observed in various parts of the vascular tree. Large conduit blood vessels vasoreactivity, ie aorta, was unaltered even in middle-aged mice emphasizing the main BH4-deletion impact on the microcirculation.


Assuntos
GTP Cicloidrolase/deficiência , Microcirculação , Microvasos/enzimologia , Fenilcetonúrias/enzimologia , Pele/irrigação sanguínea , Vasodilatação , Fatores Etários , Animais , Aorta Torácica/enzimologia , Aorta Torácica/fisiopatologia , Biopterina/análogos & derivados , Biopterina/metabolismo , Vasos Coronários/enzimologia , Vasos Coronários/fisiopatologia , Modelos Animais de Doenças , GTP Cicloidrolase/genética , Masculino , Artérias Mesentéricas/enzimologia , Artérias Mesentéricas/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microvasos/fisiopatologia , Fenilcetonúrias/genética , Fenilcetonúrias/fisiopatologia
5.
Microvasc Res ; 133: 104097, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33080248

RESUMO

This work investigates the interstitial fluid flow characteristics in a solid tumor with partial fluid leakage at the tumor surface subjected to oscillatory microvascular pressure. Solutions of the pore fluid pressure and velocity in a spherical tumor are obtained using the poroelasticity theory for small strains. It is found that partial fluid leakage at the tumor surface reduces the pore pressure drop and decreases the fluid velocity near the surface compared with those in a tumor with a fully leaking surface. Both the pore pressure and the fluid velocity decrease dramatically with an increase in the vascular frequency. The pore pressure at a vascular frequency of 1 Hz is two orders of magnitude smaller than the amplitude of the vascular pressure, and the fluid velocity at the same frequency is one order of magnitude smaller than that produced by the steady constant vascular pressure. The pore pressure amplitude may reach that of the vascular pressure under the steady state vascular pressure condition.


Assuntos
Pressão Sanguínea , Líquido Extracelular/metabolismo , Microvasos/fisiopatologia , Modelos Cardiovasculares , Neoplasias/irrigação sanguínea , Neoplasias/metabolismo , Animais , Velocidade do Fluxo Sanguíneo , Elasticidade , Humanos , Pressão Hidrostática , Porosidade
6.
Am J Physiol Heart Circ Physiol ; 320(2): H740-H761, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33337961

RESUMO

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.


Assuntos
Barreira Hematoencefálica/fisiopatologia , Cognição , Disfunção Cognitiva/fisiopatologia , Endotélio Vascular/fisiopatologia , Microvasos/fisiopatologia , Acoplamento Neurovascular , Obesidade/fisiopatologia , Fatores Etários , Idoso , Animais , Barreira Hematoencefálica/metabolismo , Envelhecimento Cognitivo , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/prevenção & controle , Disfunção Cognitiva/psicologia , Endotélio Vascular/metabolismo , Feminino , Humanos , Masculino , Microcirculação , Microvasos/metabolismo , Obesidade/epidemiologia , Obesidade/psicologia , Obesidade/terapia , Medição de Risco , Fatores de Risco
7.
Microvasc Res ; 134: 104123, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33333140

RESUMO

Although microvascular dysfunction (MVD) has been well characterized in individual organs as different disease entities, clinical evidence is mounting in support of an underlying systemic process. To address this hypothesis, we systematically searched PubMed and Medline for studies in adults published between 2014 and 2019 that measured blood biomarkers of MVD in three vital organs i.e. brain, heart, and the kidney. Of the 9706 unique articles 321 met the criteria, reporting 49 biomarkers of which 16 were common to the three organs. Endothelial dysfunction, inflammation including reactive oxidation, immune activation, and coagulation were the commonly recognized pathways. Triglyceride, C-reactive protein, Cystatin C, homocysteine, uric acid, IL-6, NT-proBNP, thrombomodulin, von Willebrand Factor, and uric acid were increased in MVD of all three organs. In contrast, vitamin D was decreased. Adiponectin, asymmetric dimethylarginine, total cholesterol, high-density and low-density cholesterol were found to be variably increased or decreased in studies. We review the pathways underlying MVD in the three organs and summarize evidence supporting its systemic nature. This scoping review informs clinicians and researchers in the multi-system manifestation of MVD. Future work should focus on longitudinal investigations to evaluate the multi-system involvement of this disease.


Assuntos
Encéfalo/irrigação sanguínea , Doenças de Pequenos Vasos Cerebrais/metabolismo , Doença da Artéria Coronariana/metabolismo , Vasos Coronários/metabolismo , Rim/irrigação sanguínea , Microvasos/metabolismo , Insuficiência Renal Crônica/metabolismo , Biomarcadores/metabolismo , Doenças de Pequenos Vasos Cerebrais/fisiopatologia , Circulação Cerebrovascular , Doença da Artéria Coronariana/fisiopatologia , Circulação Coronária , Vasos Coronários/fisiopatologia , Feminino , Humanos , Masculino , Microcirculação , Microvasos/fisiopatologia , Pessoa de Meia-Idade , Circulação Renal , Insuficiência Renal Crônica/fisiopatologia
8.
Microvasc Res ; 134: 104125, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33346023

RESUMO

Hemorrhagic shock (HS) is a severe life-threatening condition characterized by loss of blood volume and a lack of oxygen (O2) delivery to tissues. The objective of this study was to examine the impact of manipulating Starling forces in the microcirculation during HS to increase microvascular perfusion without restoring blood volume or increasing O2 carrying capacity. To decrease interstitial tissue pressure, we developed a non-contact system to locally apply negative pressure and manipulate the pressure balance in capillaries, while allowing for visualization of the microcirculation. Golden Syrian hamsters were instrumented with dorsal window chambers and subjected to a controlled hemorrhaged of 50% of the animal's blood volume without any fluid resuscitation. A negative pressure chamber was attached to the dorsal window chamber and a constant negative pressure was applied. Hemodynamic parameters (including microvascular diameter, blood flow, and functional capillary density [FCD]) were measured before and during the four hours following the hemorrhage, with and without applied negative pressure. Blood flow significantly increased in arterioles during negative pressure. The increase in flow through arterioles also improved microvascular perfusion as reflected by increased FCD. These results indicate that negative pressure increases flow in the microcirculation when fluid resuscitation is not available, thus restoring blood flow, oxygen delivery, and preventing the accumulation of metabolic waste. Applying negative pressure might allow for control of microvascular blood flow and oxygen delivery to specific tissue areas.


Assuntos
Hemodinâmica , Microcirculação , Microvasos/fisiopatologia , Choque Hemorrágico/fisiopatologia , Pele/irrigação sanguínea , Animais , Velocidade do Fluxo Sanguíneo , Modelos Animais de Doenças , Masculino , Mesocricetus , Modelos Cardiovasculares , Fluxo Sanguíneo Regional , Índice de Gravidade de Doença , Fatores de Tempo
9.
JAMA Ophthalmol ; 139(2): 182-188, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33355613

RESUMO

Importance: Noninvasive retinal imaging may detect structural changes associated with Parkinson disease (PD) and may represent a novel biomarker for disease detection. Objective: To characterize alterations in the structure and microvasculature of the retina and choroid in eyes of individuals with PD and compare them with eyes of age- and sex-matched cognitively healthy control individuals using optical coherence tomography (OCT) and OCT angiography (OCTA). Design, Setting, and Participants: This cross-sectional study was conducted at the Duke Neurological Disorders Clinic in Durham, North Carolina. Individuals aged 50 years or older with a diagnosis of PD were eligible for inclusion and underwent an evaluation and diagnosis confirmation before enrollment. Control individuals aged 50 years or older and without subjective cognitive dysfunction, a history of tremor, or evidence of motor dysfunction consistent with parkinsonism were solicited from the clinic or the Duke Alzheimer's Disease Prevention Registry. Individuals with diabetes, glaucoma, retinal pathology, other dementias, and corrected Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity worse than 20/40 Snellen were excluded. Data were analyzed between January 1, 2020, and March 30, 2020. Exposures: All participants underwent OCT and OCTA imaging. Main Outcomes and Measures: Generalized estimating equation analysis was used to characterize the association between imaging parameters and PD diagnosis. Superficial capillary plexus vessel density (VD) and perfusion density (PFD) were assessed within the ETDRS 6 × 6-mm circle, 6 × 6-mm inner ring, and 6 × 6-mm outer ring, as was the foveal avascular zone area. Peripapillary retinal nerve fiber layer thickness, macular ganglion cell-inner plexiform layer thickness, central subfield thickness, subfoveal choroidal thickness, total choroidal area, luminal area, and choroidal vascularity index (CVI) were measured. Results: A total of 124 eyes of 69 participants with PD (39 men [56.5%]; mean [SD] age, 71.7 [7.0] years) and 248 eyes of 137 control participants (77 men [56.2%]; mean [SD] age, 70.9 [6.7] years) were analyzed. In the 6 × 6-mm ETDRS circle, VD (ß coefficient = 0.37; 95% CI, 0.04-0.71; P = .03) and PFD (ß coefficient = 0.009; 95% CI, 0.0003-0.018; P = .04) were lower in eyes of participants with PD. In the inner ring of the 6 × 6-mm ETDRS circle, VD (ß coefficient = 0.61; 95% CI, 0.20-1.02; P = .003) and PFD (ß coefficient = 0.015; 95% CI, 0.005-0.026; P = .004) were lower in eyes of participants with PD. Total choroidal area (ß coefficient = -1.74 units2; 95% CI, -3.12 to -0.37 units2; P = .01) and luminal area (ß coefficient = -1.02 units2; 95% CI, -1.86 to -0.18 units2; P = .02) were greater, but CVI was lower (ß coefficient = 0.5%; 95% CI, 0.2%-0.8%; P < .001) in eyes of individuals with PD. Conclusions and Relevance: This study found that individuals with PD had decreased retinal VD and PFD as well as choroidal structural changes compared with age- and sex-matched control participants. Given the observed population differences in these noninvasive retinal biomarkers, further research into their clinical utility in PD is needed.


Assuntos
Angiografia , Corioide/irrigação sanguínea , Corioide/diagnóstico por imagem , Microvasos/diagnóstico por imagem , Doença de Parkinson/diagnóstico por imagem , Vasos Retinianos/diagnóstico por imagem , Tomografia de Coerência Óptica , Idoso , Estudos de Casos e Controles , Corioide/fisiopatologia , Estudos Transversais , Feminino , Humanos , Masculino , Microvasos/fisiopatologia , Pessoa de Meia-Idade , North Carolina , Doença de Parkinson/fisiopatologia , Valor Preditivo dos Testes , Estudos Prospectivos , Fluxo Sanguíneo Regional , Vasos Retinianos/fisiopatologia
10.
PLoS One ; 15(12): e0243737, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33362252

RESUMO

BACKGROUND: The glycocalyx is an extracellular layer lining the lumen of the vascular endothelium, protecting the endothelium from shear stress and atherosclerosis and contributes to coagulation, immune response and microvascular perfusion. The GlycoCheck system estimates glycocalyx' thickness in vessels under the tongue from perfused boundary region (PBR) and microvascular perfusion (red blood cell (RBC) filling) via a camera and dedicated software. OBJECTIVES: Evaluating reproducibility and influence of examination conditions on measurements with the GlycoCheck system. METHODS: Open, randomised, controlled study including 42 healthy smokers investigating day-to-day, side-of-tongue, inter-investigator variance, intraclass-correlation (ICC) and influence of examination conditions at intervals from 0-180 minutes on PBR and RBC filling. RESULTS: Mean (SD) age was 24.9 (6.1) years, 52% were male. There was no significant intra- or inter-investigator variation for PBR or RBC filling nor for PBR for side-of-tongue. A small day-to-day variance was found for PBR (0.012µm, p = 0.007) and RBC filling (0.003%, p = 0.005) and side-of-tongue, RBC filling (0.025%, p = 0.009). ICC was modest but highly improved by increasing measurements. Small significant influence of cigarette smoking (from 40-180 minutes), high calorie meal intake and coffee consumption was found. The latter two peaking immediately and tapering off but remained significant up to 180 minutes, highest PBR changes for the three being 0.042µm (p<0.05), 0.183µm (p<0.001) and 0.160µm (p<0.05) respectively. CONCLUSIONS: Measurements with the GlycoCheck system have a moderate reproducibility, but highly increases with multiple measurements and a small day-to-day variability. Smoking, meal and coffee intake had effects up to 180 minutes, abstinence is recommended at least 180 minutes before GlycoCheck measurements. Future studies should standardise conditions during measurements.


Assuntos
Doenças Cardiovasculares/diagnóstico , Técnicas de Diagnóstico Cardiovascular/instrumentação , Endotélio Vascular/diagnóstico por imagem , Microvasos/diagnóstico por imagem , Soalho Bucal/irrigação sanguínea , Adolescente , Adulto , Doenças Cardiovasculares/fisiopatologia , Endotélio Vascular/citologia , Endotélio Vascular/fisiopatologia , Eritrócitos/fisiologia , Feminino , Glicocálix/fisiologia , Humanos , Masculino , Microcirculação/fisiologia , Microvasos/citologia , Microvasos/fisiopatologia , Soalho Bucal/diagnóstico por imagem , Reprodutibilidade dos Testes , Fumantes , Software , Adulto Jovem
11.
PLoS One ; 15(10): e0239517, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33021999

RESUMO

Vascularized lymph node (VLN) transfer is an emerging strategy to re-establish lymphatic drainage in chronic lymphedema. However, the biological processes underlying lymph node integration remain elusive. This study introduces an experimental approach facilitating the analysis of short-term molecular and cellular effects of ischemia/reperfusion on VLN flaps. Lymph node flaps were dissected pedicled on the lateral thoracic vessels in 44 Lewis rats. VLN flaps were exposed to 45 or 120 minutes ischemia by in situ clamping of the vascular pedicle with subsequent reperfusion for 24 hours. Flaps not exposed to ischemia/reperfusion served as controls. Lymph nodes and the perinodal adipose tissue were separately analyzed by Western blot for the expression of lymphangiogenic and angiogenic growth factors. Moreover, morphology, microvessel density, proliferation, apoptosis and immune cell infiltration of VLN flaps were further assessed by histology and immunohistochemistry. Ischemia for 120 minutes was associated with a markedly reduced cellularity of lymph nodes but not of the perinodal adipose tissue. In line with this, ischemic lymph nodes exhibited a significantly lower microvessel density and an increased expression of VEGF-D and VEGF-A. However, VEGF-C expression was not upregulated. In contrast, analyses of the perinodal adipose tissue revealed a more subtle decrease of microvessel density, while only the expression of VEGF-D was increased. Moreover, after 120 minutes ischemia, lymph nodes but not the perinodal adipose tissue exhibited significantly higher numbers of proliferating and apoptotic cells as well as infiltrated macrophages and neutrophilic granulocytes compared with non-ischemic flaps. Taken together, lymph nodes of VLN flaps are highly susceptible to ischemia/reperfusion injury. In contrast, the perinodal adipose tissue is less prone to ischemia/reperfusion injury.


Assuntos
Linfonodos/irrigação sanguínea , Linfonodos/cirurgia , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Retalhos Cirúrgicos , Animais , Apoptose , Linfonodos/citologia , Microvasos/fisiopatologia , Estresse Oxidativo , Ratos , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/cirurgia
12.
Fluids Barriers CNS ; 17(1): 55, 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32912226

RESUMO

Human coronaviruses are highly pathogenic viruses that pose a serious threat to human health. Examples include the severe acute respiratory syndrome outbreak of 2003 (SARS-CoV-1), the Middle East Respiratory Syndrome (MERS-CoV) outbreak of 2012, and the current SARS-CoV-2 (COVID-19) pandemic. Herein, we review the neurological manifestations of coronaviruses and discuss the potential pathogenic role of blood-brain barrier dysfunction. We present the hypothesis that pre-existing vascular damage (due to aging, cardiovascular disease, diabetes, hypertension or other conditions) facilitates infiltration of the virus into the central nervous system (CNS), increasing neuro-inflammation and the likelihood of neurological symptoms. We also discuss the role of a neuroinflammatory cytokine profile in both blood-brain barrier dysfunction and macrovascular disease (e.g. ischemic stroke and thromboembolism). Future studies are needed to better understand the involvement of the microvasculature in coronavirus neuropathology, and to test the diagnostic potential of minimally-invasive screening tools (e.g. serum biomarkers, fluorescein retinal angiography and dynamic-contrast MRI).


Assuntos
Barreira Hematoencefálica/fisiopatologia , Infecções por Coronavirus/fisiopatologia , Inflamação/fisiopatologia , Microvasos/fisiopatologia , Doenças do Sistema Nervoso/fisiopatologia , Pneumonia Viral/fisiopatologia , Betacoronavirus , Barreira Hematoencefálica/imunologia , Barreira Hematoencefálica/virologia , Doenças Cardiovasculares/fisiopatologia , Infecções por Coronavirus/imunologia , Citocinas/imunologia , Diabetes Mellitus/fisiopatologia , Encefalite/imunologia , Encefalite/fisiopatologia , Humanos , Inflamação/imunologia , Microvasos/imunologia , Doenças do Sistema Nervoso/imunologia , Pandemias , Pneumonia Viral/imunologia , Convulsões/imunologia , Convulsões/fisiopatologia , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/fisiopatologia , Tromboembolia/imunologia , Tromboembolia/fisiopatologia
13.
Heart Lung Circ ; 29(11): 1596-1602, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32972810

RESUMO

The recently described severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected millions of people, with thousands of fatalities. It has prompted global efforts in research, with focus on the pathophysiology of coronavirus disease-19 (COVID-19), and a rapid surge of publications. COVID-19 has been associated with a myriad of clinical manifestations, including the lungs, heart, kidneys, central nervous system, gastrointestinal system, skin, and blood coagulation abnormalities. The endothelium plays a key role in organ dysfunction associated with severe infection, and current data suggest that it is also involved in SARS-CoV-2-induced sepsis. This critical review aimed to address a possible unifying mechanism underlying the diverse complications of COVID-19: microvascular dysfunction, with emphasis on the renin-angiotensin system. In addition, research perspectives are suggested in order to expand understanding of the pathophysiology of the infection.


Assuntos
Infecções por Coronavirus , Microvasos , Pandemias , Pneumonia Viral , Sistema Renina-Angiotensina/fisiologia , Betacoronavirus/fisiologia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/fisiopatologia , Humanos , Microvasos/metabolismo , Microvasos/fisiopatologia , Microvasos/virologia , Pneumonia Viral/metabolismo , Pneumonia Viral/fisiopatologia
14.
Am J Physiol Heart Circ Physiol ; 319(3): H539-H546, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32734817

RESUMO

In 2017, the American Heart Association (AHA) and American College of Cardiology (ACC) redefined stage 1 hypertension to systolic blood pressure (BP) 130-139 mmHg or diastolic BP 80-89 mmHg; however, the degree to which microvascular endothelial dysfunction is evident in adults with stage 1 hypertension remains equivocal. We tested the hypotheses that cutaneous microvascular endothelial dysfunction would be present in adults with stage 1 hypertension (HTN1) compared with normotensive adults (NTN; BP <120/<80 mmHg) but would be less severe compared with adults with stage 2 hypertension (HTN2; systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg) and that this graded impairment would be mediated by reductions in nitric oxide (NO)-dependent dilation. This retrospective analysis included 20 NTN (5 men; 45-64 yr; BP 94-114/60-70 mmHg), 22 HTN1 (11 men; 40-74 yr; BP 110-134/70-88 mmHg), and 44 HTN2 (27 men; 40-74 yr; BP 128-180/80-110 mmHg). BP and nocturnal dipping status were also assessed using 24-h ambulatory BP monitoring. Red cell flux (laser Doppler flowmetry) was measured during intradermal microdialysis perfusion of acetylcholine (ACh; 10-10 to 10-1M) alone and concurrently with the nonspecific nitric oxide (NO) synthase inhibitor NG-nitro-l-arginine methyl ester (l-NAME; 15 mM). ACh-induced dilation was impaired in HTN2 (P < 0.01), but not in HTN1 (P = 0.85), compared with NTN. Furthermore, reductions in NO-dependent dilation were evident in HTN2 (P < 0.01) but not in HTN1 (P = 0.76). Regardless of BP, endothelium-dependent dilation was impaired in nondippers (nighttime drop in systolic BP <10%) compared with dippers (nighttime drop in systolic BP ≥10%, P < 0.05). In conclusion, functional impairments in NO-mediated endothelium-dependent dilation were not evident in HTN1. However, regardless of BP classification, the lack of a nocturnal dip in BP was associated with blunted endothelium-dependent dilation.NEW & NOTEWORTHY This is the first study to pharmacologically assess the mechanistic regulation of endothelial function in adults with hypertension, classified according to the 2017 clinical guidelines set for by the American Heart Association (AHA) and American College of Cardiology (ACC). Compared with that in normotensive adults, nitric oxide-mediated endothelium-dependent dilation is impaired in adults with stage 2, but not stage 1, hypertension. Adults lacking a nighttime dip in blood pressure demonstrated reductions in endothelium-dependent dilation.


Assuntos
Pressão Sanguínea , Endotélio Vascular/fisiopatologia , Hipertensão/fisiopatologia , Microvasos/fisiopatologia , Pele/irrigação sanguínea , Vasodilatação , Adulto , Idoso , Ritmo Circadiano , Endotélio Vascular/metabolismo , Feminino , Humanos , Hipertensão/classificação , Hipertensão/diagnóstico , Masculino , Microvasos/metabolismo , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Estudos Retrospectivos , Índice de Gravidade de Doença , Fatores de Tempo
15.
Am J Physiol Heart Circ Physiol ; 319(4): H906-H914, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32857616

RESUMO

Reduced nitric oxide (NO)-mediated cutaneous vasodilation, secondary to increased oxidative stress, presents in young African American (AA) compared with European American (EA) adults and may be modulated by vitamin D status. We assessed cutaneous microvascular function in 18 young, healthy (21 ± 2 yr; 9 men, 9 women) subjects before (pre, 8 AA, 10 EA) 4 wk of 2,000 IU/day oral vitamin D supplementation and in 13 subjects after (post, 7 AA, 6 EA) 4 wk of 2,000 IU/day oral vitamin D supplementation. Serum vitamin D concentrations [25(OH)D] were measured at each visit. Three intradermal microdialysis fibers placed in the ventral forearm were randomized for treatment with 10 µM Tempol, 100 µM apocynin, or lactated Ringer's solution (control). Local heating (39°C) induced cutaneous vasodilation; red cell flux was measured at each site (laser-Doppler flowmetry), and cutaneous vascular conductance (CVC = flux/MAP) was expressed as a percentage of maximum (28 mM sodium nitroprusside, +43°C) for each phase of local heating. After stable elevated blood flow was attained, 15 mM NG-nitro-l-arginine methyl ester (l-NAME; NO synthase inhibitor) was perfused at all sites to quantify the NO contribution to cutaneous vasodilation (%NO), calculated as the difference between local heating and l-NAME plateaus. Serum [25(OH)D], the magnitude of the local heating response, and %NO were all lower in AAs versus EAs (P < 0.01). Tempol (P = 0.01), but not apocynin (P ≥ 0.19), improved the local heating response and %NO. Four weeks of supplementation improved serum [25(OH)D], the local heating response, and %NO in AAs (P ≤ 0.04) but not in EAs (P ≥ 0.41). Vitamin D supplementation mitigated endothelial dysfunction, an antecedent to overt cardiovascular disease (CVD), in otherwise healthy, young AA adults.NEW & NOTEWORTHY Endothelial dysfunction, an antecedent to overt cardiovascular disease (CVD), is observed earlier and more frequently in otherwise healthy African Americans (AAs) when compared with other ethnic groups. Vitamin D may modulate endothelial function, and darkened skin pigmentation increases risk of vitamin D deficiency. We show that 4 wk of 2,000 IU/day vitamin D supplementation improves microvascular responses to local heating in AAs. Ensuring adequate vitamin D status may mitigate development of cardiovascular dysfunction in this at-risk population.


Assuntos
Afro-Americanos , Suplementos Nutricionais , Microvasos/efeitos dos fármacos , Óxido Nítrico/metabolismo , Pele/irrigação sanguínea , Vasodilatação/efeitos dos fármacos , Deficiência de Vitamina D/tratamento farmacológico , Vitamina D/administração & dosagem , Fatores Etários , Suplementos Nutricionais/efeitos adversos , Feminino , Humanos , Masculino , Microvasos/metabolismo , Microvasos/fisiopatologia , Fatores de Tempo , Resultado do Tratamento , Vitamina D/efeitos adversos , Vitamina D/análogos & derivados , Vitamina D/sangue , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/etnologia , Deficiência de Vitamina D/fisiopatologia , Adulto Jovem
17.
Endocrinology ; 161(10)2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32603424

RESUMO

The ongoing coronavirus disease 2019 (COVID-19) pandemic is caused by the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Individuals with metabolic syndrome are at increased risk for poor disease outcomes and mortality from COVID-19. The pathophysiologic mechanisms for these observations have not been fully elucidated. A critical interaction between SARS-CoV-2 and the angiotensin-converting enzyme 2 (ACE2) facilitates viral entry into the host cell. ACE2 is expressed in pancreatic islets, vascular endothelium, and adipose tissue, and the SARS-CoV-2 -ACE2 interaction in these tissues, along with other factors, governs the spectrum and the severity of clinical manifestations among COVID-19 patients with metabolic syndrome. Moreover, the pro-inflammatory milieu observed in patients with metabolic syndrome may contribute toward COVID-19-mediated host immune dysregulation, including suboptimal immune responses, hyperinflammation, microvascular dysfunction, and thrombosis. This review describes the spectrum of clinical features, the likely pathophysiologic mechanisms, and potential implications for the management of metabolic syndrome in COVID-19 patients.


Assuntos
Infecções por Coronavirus/fisiopatologia , Síndrome Metabólica/fisiopatologia , Pneumonia Viral/fisiopatologia , Animais , Betacoronavirus/fisiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Sistema Endócrino/metabolismo , Sistema Endócrino/fisiopatologia , Humanos , Sistema Imunitário/imunologia , Sistema Imunitário/fisiopatologia , Síndrome Metabólica/imunologia , Síndrome Metabólica/metabolismo , Microvasos/fisiopatologia , Pandemias , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/imunologia , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia
18.
ACS Chem Neurosci ; 11(14): 2048-2050, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32614178

RESUMO

In COVID-19, lung manifestations present as a slowly evolving pneumonia with insidious early onset interstitial pulmonary edema that undergoes acute exacerbation in the late stages and microvascular thrombosis. Currently, these manifestations are considered to be only consequences of pulmonary SARS-CoV-2 virus infection. We are proposing a new hypothesis that neurogenic insult may also play a major role in the pathogenesis of these manifestations. SARS-CoV-2 mediated inflammation of the nucleus tractus solitarius (NTS) may play a role in the acute exacerbation of pulmonary edema and microvascular clotting in COVID-19 patients.


Assuntos
Infecções por Coronavirus/fisiopatologia , Hipotensão/fisiopatologia , Pulmão/irrigação sanguínea , Microvasos/fisiopatologia , Pneumonia Viral/fisiopatologia , Edema Pulmonar/fisiopatologia , Núcleo Solitário/fisiopatologia , Trombose/fisiopatologia , Betacoronavirus , Permeabilidade Capilar/fisiologia , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/fisiopatologia , Nervo Facial , Nervo Glossofaríngeo , Humanos , Inflamação , Pulmão/imunologia , Microvasos/imunologia , Pandemias , Sistema Nervoso Parassimpático/fisiopatologia , Pneumonia Viral/imunologia , Edema Pulmonar/imunologia , Núcleo Solitário/imunologia , Nervo Vago , Vasoconstrição
19.
Medicine (Baltimore) ; 99(29): e21177, 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32702876

RESUMO

Although dual antiplatelet therapy (DAPT) has been shown to improve index of microcirculatory resistance (IMR), the importance of the early DAPT administration on IMR and left ventricular function has not been clearly defined. In this study, we aimed to assess whether early DAPT administration affect IMR, epicardial flow, and left ventricular function in ST-segment elevation myocardial infarction (STEMI) patients undergoing percutaneous coronary intervention (PCI).This was a prospective non-randomized study on STEMI receiving primary PCI in a tertiary hospital. All subjects received loading dose DAPT (Aspirin + Clopidogrel) before primary PCI. Patients were then divided into 2 groups, the first group consists of patients receiving DAPT time ≤2 hours and the second group consists of those with DAPT time >2 hours. The primary endpoint of this study was IMR, a microvasculature function index measured quantitatively by pressure-/temperature-tipped guidewire after balloon dilatation. The secondary endpoint was the mean difference of global longitudinal strain (GLS) change at 6 months follow-up, TIMI flow before, and after PCI between the 2 groups.There were 40 subjects qualified for the study, 20 subjects in each group. There was no significant difference in IMR (50.90 [34.66] vs 58.06 [45.56], P = .579) between the 2 groups. Early administration of DAPT improved ventricular function at 6 months, reflected by statistically significant greater improvement in terms of ΔGLS (-3.48 [2.61] vs -1.23 [2.87], P = .013) and Δejection fraction (10.65% [8.74] vs -0.75% [12.83], P = .002) in the DAPT time ≤2 hours group compared with DAPT time >2 hours group. TIMI flow before PCI (P = .653) and TIMI flow after PCI (P = .205) were similar in the 2 groups.Early DAPT administration ≤2 hours may improve left ventricular function, but not IMR and TIMI flow.


Assuntos
Intervenção Coronária Percutânea/métodos , Inibidores da Agregação de Plaquetas/normas , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Fatores de Tempo , Adulto , Idoso , Feminino , Humanos , Indonésia , Masculino , Microvasos/efeitos dos fármacos , Microvasos/fisiopatologia , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/normas , Inibidores da Agregação de Plaquetas/uso terapêutico , Estudos Prospectivos , Curva ROC , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia , Função Ventricular/efeitos dos fármacos
20.
Clin Sci (Lond) ; 134(12): 1333-1356, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32542397

RESUMO

Chronic kidney disease (CKD) is a relentlessly progressive disease with a very high mortality mainly due to cardiovascular complications. Endothelial dysfunction is well documented in CKD and permanent loss of endothelial homeostasis leads to progressive organ damage. Most of the vast endothelial surface area is part of the microcirculation, but most research in CKD-related cardiovascular disease (CVD) has been devoted to macrovascular complications. We have reviewed all publications evaluating structure and function of the microcirculation in humans with CKD and animals with experimental CKD. Microvascular rarefaction, defined as a loss of perfused microvessels resulting in a significant decrease in microvascular density, is a quintessential finding in these studies. The median microvascular density was reduced by 29% in skeletal muscle and 24% in the heart in animal models of CKD and by 32% in human biopsy, autopsy and imaging studies. CKD induces rarefaction due to the loss of coherent vessel systems distal to the level of smaller arterioles, generating a typical heterogeneous pattern with avascular patches, resulting in a dysfunctional endothelium with diminished perfusion, shunting and tissue hypoxia. Endothelial cell apoptosis, hypertension, multiple metabolic, endocrine and immune disturbances of the uremic milieu and specifically, a dysregulated angiogenesis, all contribute to the multifactorial pathogenesis. By setting the stage for the development of tissue fibrosis and end organ failure, microvascular rarefaction is a principal pathogenic factor in the development of severe organ dysfunction in CKD patients, especially CVD, cerebrovascular dysfunction, muscular atrophy, cachexia, and progression of kidney disease. Treatment strategies for microvascular disease are urgently needed.


Assuntos
Doenças Cardiovasculares/epidemiologia , Microvasos/patologia , Insuficiência Renal Crônica/epidemiologia , Animais , Doenças Cardiovasculares/fisiopatologia , Comorbidade , Humanos , Hipertensão/epidemiologia , Hipertensão/fisiopatologia , Microcirculação , Microvasos/fisiopatologia , Insuficiência Renal Crônica/fisiopatologia
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