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1.
Nat Commun ; 12(1): 3091, 2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34035268

RESUMO

VEGFR2 (KDR/Flk1) signaling in endothelial cells (ECs) plays a central role in angiogenesis. The P-type ATPase transporter ATP7A regulates copper homeostasis, and its role in VEGFR2 signaling and angiogenesis is entirely unknown. Here, we describe the unexpected crosstalk between the Copper transporter ATP7A, autophagy, and VEGFR2 degradation. The functional significance of this Copper transporter was demonstrated by the finding that inducible EC-specific ATP7A deficient mice or ATP7A-dysfunctional ATP7Amut mice showed impaired post-ischemic neovascularization. In ECs, loss of ATP7A inhibited VEGF-induced VEGFR2 signaling and angiogenic responses, in part by promoting ligand-induced VEGFR2 protein degradation. Mechanistically, VEGF stimulated ATP7A translocation from the trans-Golgi network to the plasma membrane where it bound to VEGFR2, which prevented autophagy-mediated lysosomal VEGFR2 degradation by inhibiting autophagic cargo/adapter p62/SQSTM1 binding to ubiquitinated VEGFR2. Enhanced autophagy flux due to ATP7A dysfunction in vivo was confirmed by autophagy reporter CAG-ATP7Amut -RFP-EGFP-LC3 transgenic mice. In summary, our study uncovers a novel function of ATP7A to limit autophagy-mediated degradation of VEGFR2, thereby promoting VEGFR2 signaling and angiogenesis, which restores perfusion recovery and neovascularization. Thus, endothelial ATP7A is identified as a potential therapeutic target for treatment of ischemic cardiovascular diseases.


Assuntos
Autofagia/genética , Vasos Sanguíneos/metabolismo , ATPases Transportadoras de Cobre/genética , ATPases do Tipo-P/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Animais , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/fisiologia , Células COS , Células Cultivadas , Chlorocebus aethiops , ATPases Transportadoras de Cobre/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/fisiologia , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos/metabolismo , ATPases do Tipo-P/metabolismo , Interferência de RNA , Transdução de Sinais/genética , Fator A de Crescimento do Endotélio Vascular/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
2.
Nat Metab ; 3(4): 469-484, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33846639

RESUMO

Brown adipose tissue can expend large amounts of energy, and therefore increasing its size or activity is a promising therapeutic approach to combat metabolic disease. In humans, major deposits of brown fat cells are found intimately associated with large blood vessels, corresponding to perivascular adipose tissue (PVAT). However, the cellular origins of PVAT are poorly understood. Here, we determine the identity of perivascular adipocyte progenitors in mice and humans. In mice, thoracic PVAT develops from a fibroblastic lineage, consisting of progenitor cells (Pdgfra+, Ly6a+ and Pparg-) and preadipocytes (Pdgfra+, Ly6a+ and Pparg+), which share transcriptional similarity with analogous cell types in white adipose tissue. Interestingly, the aortic adventitia of adult animals contains a population of adipogenic smooth muscle cells (Myh11+, Pdgfra- and Pparg+) that contribute to perivascular adipocyte formation. Similarly, human PVAT contains presumptive fibroblastic and smooth muscle-like adipocyte progenitor cells, as revealed by single-nucleus RNA sequencing. Together, these studies define distinct populations of progenitor cells for thermogenic PVAT, providing a foundation for developing strategies to augment brown fat activity.


Assuntos
Adipócitos Marrons/fisiologia , Tecido Adiposo Marrom/fisiologia , Linhagem da Célula/fisiologia , Termogênese/fisiologia , Adipócitos Brancos/fisiologia , Adipogenia/fisiologia , Tecido Adiposo Marrom/crescimento & desenvolvimento , Animais , Animais Recém-Nascidos , Aorta/citologia , Aorta/fisiologia , Vasos Sanguíneos/fisiologia , Linhagem da Célula/genética , Fibroblastos/fisiologia , Regulação da Expressão Gênica/fisiologia , Humanos , Recém-Nascido , Camundongos , Camundongos Endogâmicos C57BL , Miócitos de Músculo Liso/fisiologia , Células-Tronco/fisiologia , Termogênese/genética
3.
Nat Protoc ; 16(4): 2158-2189, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33790475

RESUMO

Owing to their high spatiotemporal precision and adaptability to different host cells, organ-on-a-chip systems are showing great promise in drug discovery, developmental biology studies and disease modeling. However, many current micro-engineered biomimetic systems are limited in technological application because of culture media mixing that does not allow direct incorporation of techniques from stem cell biology, such as organoids. Here, we describe a detailed alternative method to cultivate millimeter-scale functional vascularized tissues on a biofabricated platform, termed 'integrated vasculature for assessing dynamic events', that enables facile incorporation of organoid technology. Utilizing the 3D stamping technique with a synthetic polymeric elastomer, a scaffold termed 'AngioTube' is generated with a central microchannel that has the mechanical stability to support a perfusable vascular system and the self-assembly of various parenchymal tissues. We demonstrate an increase in user familiarity and content analysis by situating the scaffold on a footprint of a 96-well plate. Uniquely, the platform can be used for facile connection of two or more tissue compartments in series through a common vasculature. Built-in micropores enable the studies of cell invasion involved in both angiogenesis and metastasis. We describe how this protocol can be applied to create both vascularized cardiac and hepatic tissues, metastatic breast cancer tissue and personalized pancreatic cancer tissue through incorporation of patient-derived organoids. Platform assembly to populating the scaffold with cells of interest into perfusable functional vascularized tissue will require 12-14 d and an additional 4 d if pre-polymer and master molds are needed.


Assuntos
Vasos Sanguíneos/fisiologia , Dispositivos Lab-On-A-Chip , Organoides/fisiologia , Perfusão , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Tecidos Suporte/química
4.
Nat Protoc ; 16(4): 2308-2343, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33742177

RESUMO

A major challenge in the treatment of neurodegenerative disorders is the translation of effective therapies from the lab to the clinic. One approach to improve this process is the use of human brain tissue microarray (HBTMA) technology to aid in the discovery and validation of drug targets for brain disorders. In this protocol we describe a platform for the production of high-quality HBTMAs that can be used for drug target discovery and validation. We provide examples of the use of this platform and describe detailed protocols for HBTMA design, construction and use for both protein and mRNA detection. This platform requires less tissue and reagents than single-slide approaches, greatly increasing throughput and capacity, enabling samples to be compared in a more consistent way. It takes 4 d to construct a 60 core HBTMA. Immunohistochemistry and in situ hybridization take a further 2 d. Imaging of each HBTMA slide takes 15 min, with subsequent high-content analysis taking 30 min-2 h.


Assuntos
Desenvolvimento de Medicamentos , Ensaios de Triagem em Larga Escala/métodos , Doenças Neurodegenerativas/tratamento farmacológico , Análise Serial de Tecidos/métodos , Automação , Vasos Sanguíneos/fisiologia , Humanos , Neuritos/metabolismo , Crescimento Neuronal
5.
J Vis Exp ; (168)2021 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-33616116

RESUMO

Lung histology is often used to investigate the contributions provided by airspace cells during lung homeostasis and disease pathogenesis. However, commonly used instillation-based fixation methods can displace airspace cells and mucus into terminal airways and can alter tissue morphology. In comparison, vascular perfusion-fixation techniques are superior at preserving the location and morphology of cells within airspaces and the mucosal lining. However, if positive airway pressure is not simultaneously applied, regions of the lungs may collapse and capillaries may bulge into the alveolar spaces, leading to distortion of the lung anatomy. Herein, we describe an inexpensive method for air-inflation during vascular perfusion-fixation to preserve the morphology and location of airway and alveolar cells and interstitium in murine lungs for downstream histologic studies. Constant air pressure is delivered to the lungs via the trachea from a sealed, air-filled chamber that maintains pressure via an adjustable liquid column while fixative is perfused through the right ventricle.


Assuntos
Vasos Sanguíneos/fisiologia , Pulmão/fisiologia , Perfusão , Pressão , Alvéolos Pulmonares/fisiologia , Animais , Fixadores , Camundongos
6.
Int J Mol Sci ; 22(2)2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-33466887

RESUMO

The binding of vascular endothelial growth factor A (VEGF) to VEGF receptor-2 (VEGFR-2) stimulates angiogenic signaling. Lipid rafts are cholesterol-dense regions of the plasma membrane that serve as an organizational platform for biomolecules. Although VEGFR2 has been shown to colocalize with lipid rafts to regulate its activation, the effect of lipid rafts on non-activated VEGFR2 has not been explored. Here, we characterized the involvement of lipid rafts in modulating the stability of non-activated VEGFR2 in endothelial cells using raft disrupting agents: methyl-ß-cyclodextrin, sphingomyelinase and simvastatin. Disrupting lipid rafts selectively decreased the levels of non-activated VEGFR2 as a result of increased lysosomal degradation. The decreased expression of VEGFR2 translated to reduced VEGF-activation of the extracellular signal-regulated protein kinases (ERK). Overall, our results indicate that lipid rafts stabilize VEGFR2 and its associated signal transduction activities required for angiogenesis. Thus, modulation of lipid rafts may provide a means to regulate the sensitivity of endothelial cells to VEGF stimulation. Indeed, the ability of simvastatin to down regulate VEGFR2 and inhibit VEGF activity suggest a potential mechanism underlying the observation that this drug improves outcomes in the treatment of certain cancers.


Assuntos
Células Endoteliais/metabolismo , Microdomínios da Membrana/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Anticolesterolemiantes/farmacologia , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/fisiologia , Bovinos , Células Cultivadas , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Microdomínios da Membrana/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Estabilidade Proteica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Sinvastatina/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo
7.
Am J Physiol Heart Circ Physiol ; 320(4): H1235-H1260, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33416450

RESUMO

The use of physiological models in medicine allows the evaluation of new hypotheses, development of diagnosis and clinical treatment applications, and development of training and medical education tools, as well as medical device design. Although several mathematical models of physiological systems have been presented in the literature, few of them are able to predict the human cardiorespiratory response under physical exercise stimulus adequately. This paper aims to present the building and comparison of an integrated cardiorespiratory model focused on the prediction of the healthy human response under rest and aerobic exercise. The model comprises cardiovascular circulation, respiratory mechanics, and gas exchange system, as well as cardiovascular and respiratory controllers. Every system is based on previously reported physiological models and incorporates reported mechanisms related to the aerobic exercise dynamics. Experimental data of 30 healthy male volunteers undergoing a cardiopulmonary exercise test and simulated data from two of the most current and complete cardiorespiratory models were used to evaluate the performance of the presented model. Experimental design, processing, and exploratory analysis are described in detail. The simulation results were compared against the experimental data in steady state and in transient regime. The predictions of the proposed model closely mimic the experimental data, showing in overall the lowest prediction error (10.35%), the lowest settling times for cardiovascular and respiratory variables, and in general the fastest and similar responses in transient regime. These results suggest that the proposed model is suitable to predict the cardiorespiratory response of healthy adult humans under rest and aerobic exercise conditions.NEW & NOTEWORTHY This paper presents a new cardiorespiratory model focused on the prediction of the healthy human response under rest and aerobic dynamic exercise conditions. Simulation results of cardiorespiratory variables are compared against experimental data and two of the most current and complete cardiorespiratory models.


Assuntos
Vasos Sanguíneos/fisiologia , Simulação por Computador , Exercício Físico , Coração/fisiologia , Hemodinâmica , Pulmão/fisiologia , Modelos Cardiovasculares , Respiração , Adaptação Fisiológica , Adolescente , Adulto , Aptidão Cardiorrespiratória , Humanos , Masculino , Pessoa de Meia-Idade , Descanso , Fatores de Tempo , Adulto Jovem
8.
Methods Mol Biol ; 2206: 67-88, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32754812

RESUMO

Several studies are available addressing the mechanisms of vascular morphogenesis in order to unravel how cooperative cell behavior can follow from the underlying, genetically regulated behavior of endothelial cells and from cell-to-cell and cell-to-extracellular matrix interactions. From the morphological standpoint several aspects of the process are of interest. They include the way the pattern of vessels fills the available tissue space and how the network grows during the angiogenic process, namely how a main trunk divides into smaller branches, and how branching occurs at different distances from the root point of a vascular tree. A third morphological aspect of interest concerns the spatial relationship between vessels and tissue cells able to secrete factors modulating endothelial cells self-organization, thus influencing vascular rearrangement.In the present chapter image analysis methods allowing for a quantitative characterization of these morphological aspects will be detailed and discussed. They are almost based on concepts derived from the theoretical framework represented by spatial statistics.


Assuntos
Células Endoteliais/fisiologia , Processamento de Imagem Assistida por Computador/métodos , Morfogênese/fisiologia , Neovascularização Fisiológica/fisiologia , Animais , Vasos Sanguíneos/fisiologia , Comunicação Celular/fisiologia , Embrião de Galinha , Galinhas , Matriz Extracelular/fisiologia , Microvasos/fisiologia
9.
Methods Mol Biol ; 2206: 205-222, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32754820

RESUMO

The zebrafish has emerged as a valuable and important model organism for studying vascular development and vascular biology. Here, we discuss some of the approaches used to study vessels in fish, including loss-of-function tools such as morpholinos and genetic mutants, along with methods and considerations for assessing vascular phenotypes. We also provide detailed protocols for methods used for vital imaging of the zebrafish vasculature, including microangiography and long-term time-lapse imaging. The methods we describe, and the considerations we suggest using for assessing phenotypes observed using these methods, will help ensure reliable, valid conclusions when assessing vascular phenotypes following genetic or experimental manipulation of zebrafish.


Assuntos
Angiografia/métodos , Vasos Sanguíneos/fisiologia , Peixe-Zebra/fisiologia , Animais , Vasos Sanguíneos/metabolismo , Morfolinos/metabolismo , Neovascularização Fisiológica/fisiologia , Fenótipo , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/metabolismo
10.
Nat Commun ; 11(1): 4992, 2020 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-33020487

RESUMO

Prenatal detection of congenital heart disease facilitates the opportunity for potentially life-saving care immediately after the baby is born. Echocardiography is routinely used for screening of morphological malformations, but functional measurements of blood flow are scarcely used in fetal echocardiography due to technical assumptions and issues of reliability. Magnetic resonance imaging (MRI) is readily used for quantification of abnormal blood flow in adult hearts, however, existing in utero approaches are compromised by spontaneous fetal motion. Here, we present and validate a novel method of MRI velocity-encoding combined with a motion-robust reconstruction framework for four-dimensional visualization and quantification of blood flow in the human fetal heart and major vessels. We demonstrate simultaneous 4D visualization of the anatomy and circulation, which we use to quantify flow rates through various major vessels. The framework introduced here could enable new clinical opportunities for assessment of the fetal cardiovascular system in both health and disease.


Assuntos
Coração Fetal/diagnóstico por imagem , Coração Fetal/fisiologia , Tomografia Computadorizada Quadridimensional/métodos , Imagem Cinética por Ressonância Magnética/métodos , Velocidade do Fluxo Sanguíneo , Vasos Sanguíneos/diagnóstico por imagem , Vasos Sanguíneos/fisiologia , Feminino , Idade Gestacional , Cardiopatias Congênitas/diagnóstico por imagem , Cardiopatias Congênitas/fisiopatologia , Humanos , Imagens de Fantasmas , Gravidez , Diagnóstico Pré-Natal
11.
Nat Commun ; 11(1): 5476, 2020 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-33127887

RESUMO

The formation of vascular tubes is driven by extensive changes in endothelial cell (EC) shape. Here, we have identified a role of the actin-binding protein, Marcksl1, in modulating the mechanical properties of EC cortex to regulate cell shape and vessel structure during angiogenesis. Increasing and depleting Marcksl1 expression level in vivo results in an increase and decrease, respectively, in EC size and the diameter of microvessels. Furthermore, endothelial overexpression of Marcksl1 induces ectopic blebbing on both apical and basal membranes, during and after lumen formation, that is suppressed by reduced blood flow. High resolution imaging reveals that Marcksl1 promotes the formation of linear actin bundles and decreases actin density at the EC cortex. Our findings demonstrate that a balanced network of linear and branched actin at the EC cortex is essential in conferring cortical integrity to resist the deforming forces of blood flow to regulate vessel structure.


Assuntos
Vasos Sanguíneos/anatomia & histologia , Vasos Sanguíneos/fisiologia , Proteínas de Ligação a Calmodulina/metabolismo , Células Endoteliais/metabolismo , Hemodinâmica/fisiologia , Proteínas dos Microfilamentos/metabolismo , Actinas/metabolismo , Actomiosina/metabolismo , Animais , Animais Geneticamente Modificados , Vasos Sanguíneos/citologia , Proteínas de Ligação a Calmodulina/genética , Células Endoteliais/citologia , Regulação da Expressão Gênica no Desenvolvimento , Proteínas dos Microfilamentos/genética , Modelos Animais , Transcriptoma , Peixe-Zebra/embriologia
12.
Nat Biomed Eng ; 4(9): 916-932, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32601395

RESUMO

Sacrificial templates for patterning perfusable vascular networks in engineered tissues have been constrained in architectural complexity, owing to the limitations of extrusion-based 3D printing techniques. Here, we show that cell-laden hydrogels can be patterned with algorithmically generated dendritic vessel networks and other complex hierarchical networks by using sacrificial templates made from laser-sintered carbohydrate powders. We quantified and modulated gradients of cell proliferation and cell metabolism emerging in response to fluid convection through these networks and to diffusion of oxygen and metabolites out of them. We also show scalable strategies for the fabrication, perfusion culture and volumetric analysis of large tissue-like constructs with complex and heterogeneous internal vascular architectures. Perfusable dendritic networks in cell-laden hydrogels may help sustain thick and densely cellularized engineered tissues, and assist interrogations of the interplay between mass transport and tissue function.


Assuntos
Vasos Sanguíneos/citologia , Carboidratos/química , Engenharia Tecidual/métodos , Tecidos Suporte/química , Vasos Sanguíneos/fisiologia , Proliferação de Células , Desenho de Equipamento , Hepatócitos/citologia , Humanos , Hidrogéis/química , Consumo de Oxigênio , Perfusão , Impressão Tridimensional , Engenharia Tecidual/instrumentação
13.
PLoS One ; 15(6): e0234747, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32584845

RESUMO

SUMMARY OF BACKGROUND DATA: The vascular buds in the vertebral endplate (VEP) are the structural foundation of nutrient exchange in the intervertebral disc (IVD). VEGF is closely related to angiogenesis in the endplate and intervertebral disc degeneration (IDD). OBJECTIVE: To investigate the effects of static load on vascular buds and VEGF expression in the VEP and to further clarify the relation between IDD and VEGF. METHODS: IVD motion segments were harvested from rabbit lumbar spines and cultured under no-loading conditions (controls) or in custom-made apparatuses under a constant compressive load (0.5 MPa) for up to 14 days. Tissue integrity and the number of vascular buds were determined, and the concentrations and expression of Aggrecan, COL2a1, and VEGFA in the VEPs were assessed after 3, 7, and 14 days of culturing and then compared with those of fresh tissues. RESULTS: Under the constant compression, the morphological integrity of the VEPs was gradually disrupted, and immunohistochemistry results showed a significant decrease in the levels of Agg and COL2a1. During the static load, the number of vascular buds in the VEPs was gradually reduced from the early stage of culture, and ELISA showed that the constant compressive load caused a significant decrease in the VEGFA and VEGFR2 protein concentrations, which were consistent with the immunohistochemistry results. Western blot and RT-PCR results also showed that the loading state caused a significant decrease in VEGFA expression compared with that of fresh and control samples. CONCLUSIONS: Constant compression caused degeneration of the VEP as well as a decreased number of vascular buds, thereby accelerating disc degeneration. VEGFA is involved in this process. We anticipate that regulating the expression of VEGFA may improve the condition of the lesions to the vascular buds in the endplates, thus enhancing the nutritional supply function in IVD and providing new therapeutic targets and strategies for the effective prevention and treatment of IDD.


Assuntos
Vasos Sanguíneos/fisiologia , Regulação da Expressão Gênica , Disco Intervertebral/irrigação sanguínea , Disco Intervertebral/metabolismo , Estresse Mecânico , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Técnicas de Cultura , Masculino , Coelhos
14.
Clin Sci (Lond) ; 134(12): 1491-1519, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32584404

RESUMO

Cardiovascular diseases (CVD) are the leading cause of death worldwide and aging is the primary risk factor for CVD. The development of vascular dysfunction, including endothelial dysfunction and stiffening of the large elastic arteries (i.e., the aorta and carotid arteries), contribute importantly to the age-related increase in CVD risk. Vascular aging is driven in large part by oxidative stress, which reduces bioavailability of nitric oxide and promotes alterations in the extracellular matrix. A key upstream driver of vascular oxidative stress is age-associated mitochondrial dysfunction. This review will focus on vascular mitochondria, mitochondrial dysregulation and mitochondrial reactive oxygen species (ROS) production and discuss current evidence for prevention and treatment of vascular aging via lifestyle and pharmacological strategies that improve mitochondrial health. We will also identify promising areas and important considerations ('research gaps') for future investigation.


Assuntos
Envelhecimento/fisiologia , Vasos Sanguíneos/fisiologia , Mitocôndrias/metabolismo , Animais , Vasos Sanguíneos/fisiopatologia , Humanos , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Rigidez Vascular
15.
PLoS One ; 15(6): e0233619, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32492025

RESUMO

A moderate alcohol consumption is demonstrated to exert a protective action in terms of cardiovascular risk. Although this property seems not to be beverage-specific, the various composition of alcoholic compounds could mediate peculiar effects in vivo. The aim of this study was to evaluate potential beer-mediated effects on the cardiovascular health in humans, using a meta-analytic approach (trial registration number: CRD42018118387). The literature search, comprising all English articles published until November, 30th 2019 in EMBASE, PubMed and Cochrane database included all controlled clinical trials evaluating the cardiovascular effects of beer assumption compared to alcohol-free beer, water, abstinence or placebo. Both sexes and all beer preparations were considered eligible. Outcome parameters were those entering in the cardiovascular risk charts and those related to endothelial dysfunction. Twenty-six trials were included in the analysis. Total cholesterol was significantly higher in beer drinkers compared to controls (14 studies, 3.52 mg/dL, 1.71-5.32 mg/dL). Similar increased levels were observed in high-density lipoprotein (HDL) cholesterol (18 studies, 3.63 mg/dL, 2.00-5.26 mg/dL) and in apolipoprotein A1 (5 studies, 0.16 mg/dL, 0.11-0.21 mg/dL), while no differences were detected in low density lipoprotein (LDL) cholesterol (12 studies, -2.85 mg/dL, -5.96-0.26 mg/dL) and triglycerides (14 studies, 0.40 mg/dL, -5.00-5.80 mg/dL) levels. Flow mediated dilation (FMD) resulted significantly higher in beer-consumers compared to controls (4 studies, 0.65%, 0.07-1.23%), while blood pressure and other biochemical markers of inflammation did not differ. In conclusion, the specific beer effect on human cardiovascular health was meta-analysed for the first time, highlighting an improvement of the vascular elasticity, detected by the increase of FMD (after acute intake), and of the lipid profile with a significant increase of HDL and apolipoprotein A1 serum levels. Although the long-term effects of beer consumption are not still understood, a beneficial effect of beer on endothelial function should be supposed.


Assuntos
Consumo de Bebidas Alcoólicas , Cerveja , Doenças Cardiovasculares/diagnóstico , Sistema Cardiovascular/efeitos dos fármacos , Etanol/farmacologia , Adolescente , Adulto , Idoso , Apolipoproteína A-I/sangue , Pressão Sanguínea/efeitos dos fármacos , Vasos Sanguíneos/fisiologia , Doenças Cardiovasculares/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Elasticidade/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Triglicerídeos/sangue , Vasodilatação/efeitos dos fármacos , Adulto Jovem
16.
PLoS One ; 15(6): e0234736, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32574166

RESUMO

Imaging techniques have proved to be crucial for diagnosis in reptile species. The topography of the internal organs of bearded dragons has been described in recent studies as meeting the small animal practitioners´ demand for knowledge concerning their anatomy. However, the nomenclature in the respective literature is not uniform, which could lead to misunderstandings concerning the respective and/or affected parts of the alimentary canal. Therefore, the aim of this study was to provide clear information on anatomy and histology of the alimentary canal of bearded dragons including supplying blood vessels. For the dissection of the alimentary canal, 11 Inland Bearded Dragons (Pogona vitticeps) were used (five males, six females), which had been euthanised for clinical reasons other than those concerning the digestive tract or had died spontaneously. The supplying arteries were demonstrated by injecting red latex into the aorta, while the intestinal veins were filled with blue latex via the portal vein. Microscopic examination was carried out on specimens of seven additional bearded dragons using routine histologic procedures. Macroscopically, the sections of the alimentary canal from oral to aboral were distinguished into oesophagus, stomach, small intestine, colic ampulla, colic isthmus, rectum and cloaca. Differentiation of the duodenum, jejunum and ileum was only possible when considering the bile duct, the vasculature and the histology of the organ wall. Arteries supplying the oesophagus and the final straight part of the large intestine originated from the aorta in a segmental manner. Between these, three unpaired arteries arose from the aorta. Their branches supplied stomach and intestine excluding its last part. Based on the findings of the present study, a nomenclature for the different parts of the alimentary canal and the supplying blood vessels of bearded dragons is suggested which is well understandable for veterinary practitioners and is based on zoological knowledge of reptiles.


Assuntos
Vasos Sanguíneos/anatomia & histologia , Trato Gastrointestinal/anatomia & histologia , Trato Gastrointestinal/citologia , Lagartos/anatomia & histologia , Animais , Vasos Sanguíneos/fisiologia , Feminino , Técnicas Histológicas , Masculino , Neovascularização Fisiológica
17.
Neuron ; 107(2): 306-319.e9, 2020 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-32407670

RESUMO

Melanin-concentrating hormone (MCH)-expressing neurons are key regulators of energy and glucose homeostasis. Here, we demonstrate that they provide dense projections to the median eminence (ME) in close proximity to tanycytes and fenestrated vessels. Chemogenetic activation of MCH neurons as well as optogenetic stimulation of their projections in the ME enhance permeability of the ME by increasing fenestrated vascular loops and enhance leptin action in the arcuate nucleus of the hypothalamus (ARC). Unbiased phosphoRiboTrap-based assessment of cell activation upon chemogenetic MCH neuron activation reveals MCH-neuron-dependent regulation of endothelial cells. MCH neurons express the vascular endothelial growth factor A (VEGFA), and blocking VEGF-R signaling attenuates the leptin-sensitizing effect of MCH neuron activation. Our experiments reveal that MCH neurons directly regulate permeability of the ME barrier, linking the activity of energy state and sleep regulatory neurons to the regulation of hormone accessibility to the ARC.


Assuntos
Permeabilidade da Membrana Celular/fisiologia , Hormônios Hipotalâmicos/fisiologia , Eminência Mediana/fisiologia , Melaninas/fisiologia , Neurônios/fisiologia , Hormônios Hipofisários/fisiologia , Animais , Núcleo Arqueado do Hipotálamo/fisiologia , Vasos Sanguíneos/fisiologia , Capilares/fisiologia , Núcleo Celular/fisiologia , Núcleo Celular/ultraestrutura , Células Endoteliais/fisiologia , Leptina/fisiologia , Eminência Mediana/irrigação sanguínea , Camundongos , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/biossíntese
18.
PLoS Comput Biol ; 16(4): e1007709, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32343724

RESUMO

Mechanical interactions between flowing and coagulated blood (thrombus) are crucial in dictating the deformation and remodeling of a thrombus after its formation in hemostasis. We propose a fully-Eulerian, three-dimensional, phase-field model of thrombus that is calibrated with existing in vitro experimental data. This phase-field model considers spatial variations in permeability and material properties within a single unified mathematical framework derived from an energy perspective, thereby allowing us to study effects of thrombus microstructure and properties on its deformation and possible release of emboli under different hemodynamic conditions. Moreover, we combine this proposed thrombus model with a particle-based model which simulates the initiation of the thrombus. The volume fraction of a thrombus obtained from the particle simulation is mapped to an input variable in the proposed phase-field thrombus model. The present work is thus the first computational study to integrate the initiation of a thrombus through platelet aggregation with its subsequent viscoelastic responses to various shear flows. This framework can be informed by clinical data and potentially be used to predict the risk of diverse thromboembolic events under physiological and pathological conditions.


Assuntos
Vasos Sanguíneos/fisiologia , Trombose/fisiopatologia , Biofísica/métodos , Coagulação Sanguínea/fisiologia , Plaquetas/fisiologia , Simulação por Computador , Humanos , Modelos Biológicos , Adesividade Plaquetária/fisiologia , Agregação Plaquetária/fisiologia , Trombose/sangue
19.
Sci Rep ; 10(1): 6929, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32332779

RESUMO

Tube-shaped blood vessel models that mimic their geometries and mechanical properties can deliver reliable and realistic behavioral information such as deformation and rupture during procedures such as insertion of medical devices. Thickness of vessel walls is an important parameter for fabricating the blood vessel models owing to their strong influence on the model behavior, especially during deformation. The dip-coating method is used to fabricate blood vessel models; however, non-uniform wall thicknesses are observed using this method. This study aimed at finding the characteristics of stereo "angular control dip-coating" (ACDC) system to develop a dip-coating system that can produce tubular models with uniformed wall thickness. The system developed here enables an observation of the substrate behavior from two different views. The conditions of dip-coating used in this study produce 1.36-1.82 mm in the maximum and 0.188-0.435 mm in minimum wall thickness and the fabricated walls cover the realistic range of carotid arterial dimensions. The characteristics of the ACDC system indicate that ACDC is effective for fabricating the uniform wall thickness particularly in the strong curved parts.


Assuntos
Vasos Sanguíneos/fisiologia , Modelos Biológicos , Engenharia Tecidual/métodos , Álcool de Polivinil/química , Microtomografia por Raio-X
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