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1.
Nutrients ; 13(8)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34444906

RESUMO

Diabetic kidney disease (DKD) has become a global health concern, with about 40% of people living with type 1 and type 2 diabetes mellitus developing DKD. Upregulation of vascular endothelial growth factor (VEGF) in the kidney is a significant pathology of DKD associated with increased glomerular vascular permeability. To date, however, current anti-VEGF therapies have demonstrated limited success in treating DKD. Recent studies have shown that artificial sweeteners exhibit anti-VEGF potential. The aim of this study was therefore to assess the effects of aspartame, saccharin, and sucralose on VEGF-induced leak using an in vitro model of the glomerular endothelium. Saccharin and sucralose but not aspartame protected against VEGF-induced permeability. Whilst the sweeteners had no effect on traditional VEGF signalling, GC-MS analysis demonstrated that the sweetener sucralose was not able to enter the glomerular endothelial cell to exert the protective effect. Chemical and molecular inhibition studies demonstrated that sweetener-mediated protection of the glomerular endothelium against VEGF is dependent on the sweet taste receptor, T1R3. These studies demonstrate the potential for sweeteners to exert a protective effect against VEGF-induced increased permeability to maintain a healthy endothelium and protect against vascular leak in the glomerulus in settings of DKD.


Assuntos
Permeabilidade Capilar/efeitos dos fármacos , Substâncias Protetoras/farmacocinética , Sacarina/farmacocinética , Sacarose/análogos & derivados , Edulcorantes/farmacologia , Aspartame/farmacocinética , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Células Endoteliais , Endotélio Vascular/metabolismo , Humanos , Técnicas In Vitro , Rim/irrigação sanguínea , Microvasos/metabolismo , Sacarose/farmacocinética , Fatores de Crescimento do Endotélio Vascular/metabolismo
2.
Am J Physiol Heart Circ Physiol ; 321(3): H592-H598, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34415188

RESUMO

The endothelin-B (ETB) receptor is a key regulator of vascular endothelial function in women. We have previously shown that the ETB receptor mediates vasodilation in young women, an effect that is lost after menopause. However, the direct impact of changes in estradiol (E2) on ETB receptor function in women remains unclear. Therefore, the purpose of this study was to test the hypothesis that E2 exposure modulates ETB receptor-mediated dilation in young women. Fifteen young women (24 ± 4 yr, 24 ± 3 kg/m2) completed the study. Endogenous sex hormone production was suppressed with daily administration of a gonadotropin-releasing hormone antagonist (GnRHant; Ganirelix) for 10 days; E2 (0.1 mg/day, Vivelle-Dot patch) was added back on days 4-10. We measured vasodilation in the cutaneous microcirculation (microvascular endothelial function) via local heating (42°C) on day 4 (GnRHant) and day 10 (GnRHant + E2) using laser Doppler flowmetry coupled with intradermal microdialysis during perfusions of lactated Ringer's (control) and ETB receptor antagonist (BQ-788, 300 nM). During GnRHant, vasodilatory responses to local heating were enhanced with ETB receptor blockade (control: 83 ± 9 vs. BQ-788: 90 ± 5%CVCmax, P = 0.004). E2 administration improved vasodilation in the control site (GnRHant: 83 ± 9 vs. GnRHant + E2: 89 ± 8%CVCmax, P = 0.036). Furthermore, cutaneous vasodilatory responses during ETB receptor blockade were blunted after E2 administration (control: 89 ± 8 vs. BQ-788: 84 ± 8%CVCmax, P = 0.047). These data demonstrate that ovarian hormones, specifically E2, modulate ETB receptor function and contribute to the regulation of microvascular endothelial function in young women.NEW & NOTEWORTHY The endothelin-B (ETB) receptor mediates vasodilation in young women, an effect lost following menopause. It is unclear whether these alterations are due to aging or changes in estradiol (E2). During endogenous hormone suppression (GnRH antagonist), blockade of ETB receptors enhanced cutaneous microvascular vasodilation. However, during E2 administration, blockade of ETB receptors attenuated vasodilation, indicating that the ETB receptor mediates dilation in the presence of E2. In young women, ETB receptors mediate vasodilation in the presence of E2, an effect that is lost when E2 is suppressed.


Assuntos
Antagonistas do Receptor de Endotelina B/farmacologia , Estradiol/farmacologia , Estrogênios/farmacologia , Receptor de Endotelina B/metabolismo , Vasodilatação , Adulto , Feminino , Hormônio Liberador de Gonadotropina/análogos & derivados , Hormônio Liberador de Gonadotropina/farmacologia , Antagonistas de Hormônios/farmacologia , Humanos , Microvasos/efeitos dos fármacos , Microvasos/metabolismo , Microvasos/fisiologia , Oligopeptídeos/farmacologia , Piperidinas/farmacologia , Pele/irrigação sanguínea
3.
Mol Med Rep ; 24(4)2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34328190

RESUMO

Pulmonary microvascular endothelial cell (PMVEC) apoptosis is the initial stage of adult pulmonary hypertension (PH), which involves high pulmonary arterial pressure and pulmonary vascular remodeling. However, the mechanism regulating PMVEC apoptosis and its involvement in the early stages of neonatal hypoxic PH (HPH) pathogenesis are currently unclear. The present study aimed to investigate the effects of heat shock protein 70 (HSP70) on hypoxia­induced apoptosis in PMVECs. PMVECs isolated from neonatal Sprague­Dawley rats were transfected with lentivirus with or without HSP70, or treated with the synthetic HSP70 inhibitor N­formyl­3,4­methylenedioxy­benzylidene-g-butyrolactam under hypoxic conditions (5% O2) for 24, 48 or 72 h. PMVEC apoptosis was evaluated by performing flow cytometry and mitochondrial membrane potential (MMP) assays. The expression levels of HSP70, hypoxia­inducible factor­1α (HIF­1α) and apoptosis­associated proteins were determined by conducting reverse transcription­quantitative PCR and western blotting. Following 24, 48 or 72 h of hypoxia, the apoptotic rates of PMVECs were significantly elevated compared with cells under normoxic conditions. The MMP was significantly reduced, whereas the mRNA and protein expression levels of HIF­1α, cytochrome c (cyt C), caspase­3 and HSP70 were enhanced by hypoxia compared with those under normoxic conditions. Additionally, the mRNA and protein expression levels of B­cell lymphoma 2 (Bcl­2) were significantly downregulated in the hypoxia group compared with those in the normoxia group. In hypoxic PMVECs, HSP70 overexpression decreased the apoptotic rate and the expression levels of cyt C, downregulated the expression levels of caspase­3 and HIF­1α, and increased the MMP and the expression levels of Bcl­2. HSP70 inhibition resulted in the opposite outcomes compared with those of HSP70 overexpression. Therefore, the results of the present study suggested that HSP70 may inhibit mitochondrial pathway­mediated apoptosis in isolated neonatal rat PMVECs in early­stage hypoxia, which may be associated with HSP70­mediated HIF­1α downregulation. Overall, HSP70 may be protective against neonatal HPH through the HSP70/HIF­1α pathway.


Assuntos
Apoptose/genética , Células Endoteliais/metabolismo , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Hipertensão Pulmonar/metabolismo , Microvasos/metabolismo , Animais , Animais Recém-Nascidos , Caspase 3/genética , Caspase 3/metabolismo , Hipóxia Celular , Regulação para Baixo , Células Endoteliais/citologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Metaloproteinases da Matriz/metabolismo , Microvasos/citologia , Mitocôndrias/metabolismo , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/genética , Regulação para Cima
4.
Theranostics ; 11(14): 6766-6785, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093852

RESUMO

Endothelial cells (ECs) constitute the innermost layer in all blood vessels to maintain the structural integrity and microcirculation function for coronary microvasculature. Impaired endothelial function is demonstrated in various cardiovascular diseases including myocardial infarction (MI), which is featured by reduced myocardial blood flow as a result of epicardial coronary obstruction, thrombogenesis, and inflammation. In this context, understanding the cellular and molecular mechanisms governing the function of coronary ECs is essential for the early diagnosis and optimal treatment of MI. Although ECs contain relatively fewer mitochondria compared with cardiomyocytes, they function as key sensors of environmental and cellular stress, in the regulation of EC viability, structural integrity and function. Mitochondrial quality control (MQC) machineries respond to a broad array of stress stimuli to regulate fission, fusion, mitophagy and biogenesis in mitochondria. Impaired MQC is a cardinal feature of EC injury and dysfunction. Hence, medications modulating MQC mechanisms are considered as promising novel therapeutic options in MI. Here in this review, we provide updated insights into the key role of MQC mechanisms in coronary ECs and microvascular dysfunction in MI. We also discussed the option of MQC as a novel therapeutic target to delay, reverse or repair coronary microvascular damage in MI. Contemporary available MQC-targeted therapies with potential clinical benefits to alleviate coronary microvascular injury during MI are also summarized.


Assuntos
Células Endoteliais/metabolismo , Microvasos/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Dinâmica Mitocondrial/efeitos dos fármacos , Infarto do Miocárdio/metabolismo , Animais , Humanos , Inflamação/metabolismo , Microvasos/patologia , Mitocôndrias/genética , Dinâmica Mitocondrial/genética , Mitofagia/genética , Infarto do Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
5.
J Dermatol Sci ; 103(1): 25-32, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34148739

RESUMO

BACKGROUND: Mucopolysaccharide polysulfate (MPS) is a heparinoid and MPS-containing formulations are widely used as moisturizers for dry skin and to treat peripheral vascular insufficiency. Although MPS has therapeutic effects in skin diseases with microvascular abnormalities, the effects of MPS on microvascular function remain incompletely understood. OBJECTIVE: The aim of this study was to evaluate the functional activities of MPS on human pericytes (HPC) and human dermal microvascular endothelial cells (HDMEC) in vitro, and on microvascular permeability of the skin. METHODS: The protein expression of angiopoietin (Ang)-1 in HPC, and platelet-derived growth factor-BB (PDGF-BB) and phosphorylated tyrosine-protein kinase receptor 2 (Tie2) in HDMEC were measured in the presence or absence of MPS. The vascular barrier was evaluated by the expressions of claudin-5 and vascular endothelial (VE)-cadherin, and transendothelial electrical resistance (TEER). RESULTS: In HPC, MPS dose-dependently enhanced Ang-1 secretion, which activated Tie2 in HDMEC. In HDMEC, MPS significantly increased the production of PDGF-BB, which is important for the recruitment of HPC to the vascular endothelium, and significantly increased the phosphorylation of Tie2, which results in the activation of the Ang-1/Tie2 signaling . MPS significantly increased the expression of tight junction protein claudin-5 and TEER in the HDMEC. Moreover, the intradermal injection of MPS prevented vascular endothelial growth factor-induced increase in vascular permeability in mouse skin. CONCLUSION: We found that MPS promoted microvascular stabilization and barrier integrity in HDMEC via Ang-1/Tie2 activation. These results suggest that MPS might improve microvascular abnormalities in various diseases accompanied by disturbances in Ang-1/Tie2 signaling.


Assuntos
Permeabilidade Capilar/efeitos dos fármacos , Emolientes/farmacologia , Endotélio Vascular/efeitos dos fármacos , Glicosaminoglicanos/farmacologia , Microvasos/efeitos dos fármacos , Angiopoietina-1/metabolismo , Animais , Becaplermina/metabolismo , Células Endoteliais , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Feminino , Humanos , Injeções Intradérmicas , Camundongos , Microvasos/citologia , Microvasos/metabolismo , Modelos Animais , Pericitos , Fosforilação/efeitos dos fármacos , Receptor TIE-2/metabolismo , Pele/irrigação sanguínea , Pele/efeitos dos fármacos , Pele/metabolismo , Dermatopatias Vasculares/tratamento farmacológico
6.
Int J Mol Sci ; 22(10)2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-34067629

RESUMO

Tissue-nonspecific alkaline phosphatase (TNAP) is an ectoenzyme bound to the plasma membranes of numerous cells via a glycosylphosphatidylinositol (GPI) moiety. TNAP's function is well-recognized from earlier studies establishing its important role in bone mineralization. TNAP is also highly expressed in cerebral microvessels; however, its function in brain cerebral microvessels is poorly understood. In recent years, few studies have begun to delineate a role for TNAP in brain microvascular endothelial cells (BMECs)-a key component of cerebral microvessels. This review summarizes important information on the role of BMEC TNAP, and its implication in health and disease. Furthermore, we discuss current models and tools that may assist researchers in elucidating the function of TNAP in BMECs.


Assuntos
Fosfatase Alcalina/metabolismo , Células Endoteliais/metabolismo , Microvasos/metabolismo , Fosfatase Alcalina/fisiologia , Animais , Encéfalo/metabolismo , Sistema Nervoso Central/metabolismo , Humanos
7.
Am J Physiol Cell Physiol ; 321(2): C214-C220, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34161151

RESUMO

Endothelial hyperpermeability is the hallmark of acute respiratory distress syndrome (ARDS). Laborious efforts in the investigation of the molecular pathways involved in the regulation of the vascular barrier shall reveal novel therapeutic targets toward that respiratory disorder. Herein, we investigate in vitro the effects of the α-1,2-mannosidase 1 inhibitor kifunensine (KIF) and brefeldin A (BFA) in the lipopolysaccharides (LPS)-induced endothelial breakdown. Our results suggest that BFA opposes the deteriorating effects of KIF [unfolded protein response (UPR) suppressor] toward the lung microvasculature. Since KIF is a UPR suppressor, and brefeldin A is a UPR inducer, we suggest that a carefully devised UPR manipulation may deliver novel therapeutic avenues in diseases related to endothelial barrier dysfunction (e.g., ARDS and sepsis).


Assuntos
Alcaloides/metabolismo , Brefeldina A/metabolismo , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Permeabilidade/efeitos dos fármacos , Animais , Bovinos , Células Endoteliais/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Humanos , Lipopolissacarídeos/farmacologia , Pulmão/metabolismo , Microvasos/efeitos dos fármacos , Microvasos/metabolismo , Síndrome do Desconforto Respiratório/tratamento farmacológico , Síndrome do Desconforto Respiratório/metabolismo
8.
Int J Mol Sci ; 22(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070679

RESUMO

Hemolytic uremic syndrome (HUS) is characterized by a triad of symptoms consisting of hemolytic anemia, thrombocytopenia and acute renal failure. The most common form of HUS is caused by an infection with Shiga toxin (Stx) producing Escherichia coli bacteria (STEC-HUS), and the kidneys are the major organs affected. The development of HUS after an infection with Stx occurs most frequently in children under the age of 5 years. However, the cause for the higher incidence of STEC-HUS in children compared to adults is still not well understood. Human glomerular microvascular endothelial cells (HGMVECs) isolated and cultured from pediatric and adult kidney tissue were investigated with respect to Stx binding and different cellular responses. Shiga toxin-1 (Stx-1) inhibited protein synthesis in both pediatric and adult HGMVECs in a dose-dependent manner at basal conditions. The preincubation of pediatric and adult HGMVECs for 24 hrs with TNFα resulted in increased Stx binding to the cell surface and a 20-40% increase in protein synthesis inhibition in both age groups. A decreased proliferation of cells was found when a bromodeoxyuridine (BrdU) assay was performed. A trend towards a delay in endothelial wound closure was visible when pediatric and adult HGMVECs were incubated with Stx-1. Although minor differences between pediatric HGMVECs and adult HGMVECs were found in the assays applied in this study, no significant differences were observed. In conclusion, we have demonstrated that in vitro primary HGMVECs isolated from pediatric and adult kidneys do not significantly differ in their cell biological responses to Stx-1.


Assuntos
Células Endoteliais/metabolismo , Mesângio Glomerular/metabolismo , Microvasos/metabolismo , Toxina Shiga I/toxicidade , Adulto , Células Cultivadas , Pré-Escolar , Relação Dose-Resposta a Droga , Células Endoteliais/patologia , Feminino , Mesângio Glomerular/patologia , Humanos , Masculino , Microvasos/patologia
9.
Biochem Biophys Res Commun ; 559: 222-229, 2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-33962209

RESUMO

As one of the natural triterpenoids isolated from Anemone Raddeana Regel, Raddeanin A (RA) has been confirmed to possess therapeutic effects against multiple tumorigeneses, especially for the onset of glioblastoma and growth in human brains. However, the mechanism by which this happens remains poorly understood in terms of the vascular endothelium trafficking routine of RA through the brain-blood barrier (BBB). To seek such answers, human brain microenvironment endothelial cells (HBMECs) were used to stimulate the microenvironment in vitro, and to explore the intracellular accumulation of RA. The results of this experiment illustrated that RA has a relative moderate transport affinity for such cells. The kinetic parameter Km was 37.01 ± 2.116 µM and Vmax was 9.412 ± 0.1375 nM/min/mg of protein. Interestingly, protein downregulation of P-glycoprotein (P-gp, ABCB1/MDR1) significantly activated RA transmembrane activity, which proves that P-gp is responsible for RA cellular trafficking. In addition, the selective non-specific inhibitor, LY335979 increased either RA or the classical substrate of P-gp, digoxin, intracellular accumulation by restricting the transporter's function but without jeopardizing cytomembrane proteins. Moreover, a decrease in the expression or activity of P-gp triggered RA drug resistance to HBMECs. In summary, our data showed that both the expression and function of P-gp are all necessary for RA transmembrane trafficking through cerebrovascular endothelial cells. This study provides significant evidence for the presence of a connection between RA transport and P-gp variation during drug BBB penetration. It is also suggesting some vital guidance on the RA pharmacodynamic effect in human brains.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Encéfalo/irrigação sanguínea , Células Endoteliais/metabolismo , Saponinas/metabolismo , Transporte Biológico , Resistência a Medicamentos , Humanos , Espaço Intracelular/metabolismo , Microvasos/metabolismo
10.
Folia Histochem Cytobiol ; 59(2): 108-113, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34003485

RESUMO

INTRODUCTION: Endothelial dysfunction is a critical part of heart failure (HF) pathophysiology. It is not clear, however, whether it is present at the similar level in the early and late HF stages. MATERIAL AND METHODS: von Willebrand factor (vWF) and its mRNA levels in biopsies of non-ischemic patients with HF secondary to dilated cardiomyopathy were studied. Consecutive patients with HF were divided into two groups: group A with disease duration ≤ 12 months (n = 59) and group B with disease duration > 12 months (n = 68). The immunoreactivity of the vWF was compared with autopsy sections of 19 control cases. Tissue vWF gene expression was analyzed at the mRNA level by RT-PCR. RESULTS: In the group A, there was lower vWF immunoreactivity in the coronary microvessels compared to the group B [1.5 (1.0-2.0) vs. 2.0 (1.5-2.4), P = 0.001]. In the control group, only weak vWF expression was observed. Protein expression was not accompanied by vWF mRNA whose levels were significantly higher in the Group A as compared to the Group B [14671 (4932-51561) vs. 3643 (185.3-9030.8), P = 0.005]. Protein vWF expression was inversely associated with its mRNA levels (r = -0.34, P = 0.04). CONCLUSIONS: High myocardial protein expression of vWF in patients with long-lasting HF symptoms may highlight the persistent nature of endothelial dysfunction in such a cohort of patients.


Assuntos
Endotélio Vascular/metabolismo , Insuficiência Cardíaca/metabolismo , Miocárdio/metabolismo , Fator de von Willebrand/metabolismo , Adulto , Vasos Coronários/metabolismo , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Masculino , Microvasos/metabolismo , Pessoa de Meia-Idade , Regulação para Cima
11.
Clin Transl Gastroenterol ; 12(5): e00333, 2021 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-33908373

RESUMO

INTRODUCTION: Microvesicles (MVs) with procoagulant properties may favor liver parenchymal extinction, then cirrhosis-related complications and mortality. In a longitudinal cohort of cirrhotic patients, we measured plasma levels of platelet-derived MVs (PMVs), endothelial-derived MVs, and red blood cell-derived MVs, expressing phosphatidylserine (annexin V-positive [AV+]) or not, and evaluated their impact on Model for End-Stage Liver Disease (MELD) score and transplant-free survival. METHODS: MVs were quantified using flow cytometry in plasma from 90 noninfected cirrhotic patients and 10 healthy volunteers matched for age and sex. Impact of plasma microvesicle levels on 6-month transplant-free survival was assessed using log-rank tests and logistic regression. RESULTS: Microvesicle levels, mostly platelet-derived, were 2.5-fold higher in healthy volunteers compared with cirrhotic patients. Circulating small AV+ PMV levels were lower in cirrhotic patients (P = 0.014) and inversely correlated with MELD scores (R = -0.28; P = 0.0065). During 1-year follow-up, 8 patients died and 7 underwent liver transplantation. In the remaining patients, circulating microvesicle levels did not change significantly. Six-month transplant-free survival was lower in patients with low baseline small AV+ PMV levels (72.6% vs 96.2%; P = 0.0007). In multivariate analyses adjusted for age, ascites, esophageal varices, encephalopathy, clinical decompensation, total platelet counts, MELD score, and/or Child-Pugh C stage, patients with lower small AV+ PMV levels had a significant 5- to 8-fold higher risk of 6-month death or liver transplant. Other PMV levels did not impact on survival. DISCUSSION: Decreased circulating small AV+ PMV levels are associated with significantly lower transplant-free survival in cirrhotic patients independently of MELD score and platelet counts.


Assuntos
Anexina A5/sangue , Plaquetas/metabolismo , Cirrose Hepática/sangue , Microvasos/metabolismo , Idoso , Estudos de Casos e Controles , Endotélio Vascular/metabolismo , Eritrócitos/metabolismo , Feminino , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/cirurgia , Transplante de Fígado , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Análise de Sobrevida
12.
Cell Mol Life Sci ; 78(11): 4867-4891, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33825942

RESUMO

Duchenne muscular dystrophy (DMD) is a devastating chromosome X-linked disease that manifests predominantly in progressive skeletal muscle wasting and dysfunctions in the heart and diaphragm. Approximately 1/5000 boys and 1/50,000,000 girls suffer from DMD, and to date, the disease is incurable and leads to premature death. This phenotypic severity is due to mutations in the DMD gene, which result in the absence of functional dystrophin protein. Initially, dystrophin was thought to be a force transducer; however, it is now considered an essential component of the dystrophin-associated protein complex (DAPC), viewed as a multicomponent mechanical scaffold and a signal transduction hub. Modulating signal pathway activation or gene expression through epigenetic modifications has emerged at the forefront of therapeutic approaches as either an adjunct or stand-alone strategy. In this review, we propose a broader perspective by considering DMD to be a disease that affects myofibers and muscle stem (satellite) cells, as well as a disorder in which abrogated communication between different cell types occurs. We believe that by taking this systemic view, we can achieve safe and holistic treatments that can restore correct signal transmission and gene expression in diseased DMD tissues.


Assuntos
Comunicação Celular , Distrofina/metabolismo , Distrofia Muscular de Duchenne/patologia , Transdução de Sinais , Animais , Osso e Ossos/metabolismo , Distrofina/química , Distrofina/genética , Humanos , Microvasos/metabolismo , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/terapia , Neurônios/metabolismo , Transdução de Sinais/genética
13.
Front Immunol ; 12: 586429, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33815358

RESUMO

Angiogenesis is an important process under both physiological and pathophysiological conditions. Here we investigated the role and the underlying mechanism of PD-1 in hindlimb ischemia-induced inflammation and angiogenesis in mice. We found that inhibition of PD-1 by genetic PD-1 knockout or pharmacological PD-1 blocking antibodies dramatically attenuated hindlimb blood perfusion, angiogenesis, and exercise capacity in mice after femoral artery ligation. Mechanistically, we found that PD-1 knockout significantly exacerbated ischemia-induced muscle oxidative stress, leukocyte infiltration and IFN-γ production before abnormal angiogenesis in these mice. In addition, we found that the percentages of IFN-γ positive macrophages and CD8 T cells were significantly increased in P-1 knockout mice after hindlimb ischemia. Macrophages were the major leukocyte subset infiltrated in skeletal muscle, which were responsible for the enhanced muscle leukocyte-derived IFN-γ production in PD-1 knockout mice after hindlimb ischemia. Moreover, we demonstrated that IFN-γ significantly attenuated vascular endothelial cell proliferation, tube formation and migration in vitro. IFN-γ also significantly enhanced vascular endothelial cell apoptosis. In addition, the total number of TNF-α positive leukocytes/muscle weight were significantly increased in PD-1-/- mice after hindlimb ischemia. These data indicate that PD-1 exerts an important role in ischemia-induced muscle inflammation and angiogenesis.


Assuntos
Inibidores de Checkpoint Imunológico/farmacologia , Isquemia/complicações , Miosite/etiologia , Miosite/patologia , Neovascularização Patológica/etiologia , Estresse Oxidativo/efeitos dos fármacos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Membro Posterior/irrigação sanguínea , Interferon gama/metabolismo , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Leucócitos/metabolismo , Camundongos , Camundongos Knockout , Microvasos/efeitos dos fármacos , Microvasos/metabolismo , Microvasos/patologia , Miosite/tratamento farmacológico , Miosite/metabolismo , Neovascularização Patológica/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
14.
FASEB J ; 35(5): e21512, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33811692

RESUMO

Vascular rarefaction due to impaired angiogenesis is associated with contractile dysfunction and the transition from compensation to decompensation and heart failure. The regulatory mechanism controlling vascular rarefaction during the transition remains elusive. Increased expression of a nuclear RNA-binding protein CUGBP Elav-like family member 1 (CELF1) in the adult heart is associated with the transition from compensated hypertrophy to decompensated heart failure. Elevated CELF1 level resulted in degradation of the major cardiac gap junction protein, connexin 43, in dilated cardiomyopathy (DCM), the most common cause of heart failure. In the present study, we investigated the role of increased CELF1 expression in causing vascular rarefaction in DCM. CELF1 overexpression (CELF1-OE) in cardiomyocytes resulted in reduced capillary density. CELF1-OE mice administered hypoxyprobe showed immunoreactivity and increased mRNA levels of HIF1α, Glut-1, and Pdk-1, which suggested the association of a reduced capillary density-induced hypoxic condition with CELF1 overexpression. Vegfa mRNA level was downregulated in mouse hearts exhibiting DCM, including CELF1-OE and infarcted hearts. Vegfa mRNA level was also downregulated to a similar extent in cardiomyocytes isolated from infarcted hearts by Langendorff preparation, which suggested cardiomyocyte-derived Vegfa expression mediated by CELF1. Cardiomyocyte-specific depletion of CELF1 preserved the capillary density and Vegfa mRNA level in infarcted mouse hearts. Also, CELF1 bound to Vegfa mRNA and regulated Vegfa mRNA stability via the 3' untranslated region. These results suggest that elevated CELF1 level has dual effects on impairing the functions of cardiomyocytes and microvasculature in DCM.


Assuntos
Proteínas CELF1/metabolismo , Insuficiência Cardíaca/patologia , Microvasos/patologia , Proteólise , Estabilidade de RNA , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Proteínas CELF1/genética , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microvasos/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética
16.
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 , Densidade Microvascular , 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
17.
Cell Mol Life Sci ; 78(9): 4377-4398, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33688979

RESUMO

The cerebral vasculature plays a central role in human health and disease and possesses several unique anatomic, functional and molecular characteristics. Despite their importance, the mechanisms that determine cerebrovascular development are less well studied than other vascular territories. This is in part due to limitations of existing models and techniques for visualisation and manipulation of the cerebral vasculature. In this review we summarise the experimental approaches used to study the cerebral vessels and the mechanisms that contribute to their development.


Assuntos
Encéfalo/crescimento & desenvolvimento , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/irrigação sanguínea , Encéfalo/metabolismo , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Matriz Extracelular/metabolismo , Humanos , Microvasos/crescimento & desenvolvimento , Microvasos/metabolismo , Modelos Cardiovasculares , Neovascularização Fisiológica , Transdução de Sinais
18.
Int J Biochem Cell Biol ; 134: 105971, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33775914

RESUMO

Pericytes (PC) are microvascular mural cells that make specific cell-to-cell contacts with the endothelial cells (EC). These cells are obligatory constituents of the microvessels including the retinal vasculature and they serve as regulators of vascular development, stabilization, maturation and remodeling. During early stages of diabetic retinopathy (DR), apoptotic loss of PC surrounding the retinal vasculature occurs. This may lead to reduced vessel stability, the onset of EC apoptosis, and subsequent retinal ischemia leading to angiogenesis and eventually, severe vision loss due to late proliferative diabetic retinopathy (PDR). Similarly, diabetic nephropathy (DN) is a chronic kidney disease due to hyperglycemia that particularly affects renal PC. Chronic high blood glucose level causes migration of peritubular PC away from the capillary into the interstitial space, which destabilizes the micro vessels, resulting in microvascular rarefaction. In both diabetes associated complications, the identification of specific biomarkers is necessary to stabilize the PC at an early stage. This review largely covers the importance of PC towards the pathogenesis of diabetes associated complications, and their heterogeneity in healthy and angiogenic vasculature.


Assuntos
Diabetes Mellitus/fisiopatologia , Nefropatias Diabéticas/patologia , Retinopatia Diabética/patologia , Células Endoteliais/patologia , Microvasos/patologia , Neovascularização Patológica/patologia , Pericitos/patologia , Animais , Apoptose/fisiologia , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/metabolismo , Retinopatia Diabética/epidemiologia , Retinopatia Diabética/metabolismo , Células Endoteliais/metabolismo , Humanos , Microvasos/metabolismo , Pericitos/metabolismo
19.
Neuron ; 109(7): 1168-1187.e13, 2021 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-33657412

RESUMO

The microvasculature underlies the supply networks that support neuronal activity within heterogeneous brain regions. What are common versus heterogeneous aspects of the connectivity, density, and orientation of capillary networks? To address this, we imaged, reconstructed, and analyzed the microvasculature connectome in whole adult mice brains with sub-micrometer resolution. Graph analysis revealed common network topology across the brain that leads to a shared structural robustness against the rarefaction of vessels. Geometrical analysis, based on anatomically accurate reconstructions, uncovered a scaling law that links length density, i.e., the length of vessel per volume, with tissue-to-vessel distances. We then derive a formula that connects regional differences in metabolism to differences in length density and, further, predicts a common value of maximum tissue oxygen tension across the brain. Last, the orientation of capillaries is weakly anisotropic with the exception of a few strongly anisotropic regions; this variation can impact the interpretation of fMRI data.


Assuntos
Circulação Cerebrovascular/fisiologia , Microvasos/anatomia & histologia , Microvasos/metabolismo , Algoritmos , Animais , Anisotropia , Encéfalo/diagnóstico por imagem , Química Encefálica/fisiologia , Capilares/fisiologia , Corantes Fluorescentes , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microvasos/diagnóstico por imagem , Consumo de Oxigênio/fisiologia
20.
Food Funct ; 12(6): 2715-2725, 2021 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-33667286

RESUMO

The microvasculature endothelium accurately regulates the passage of molecules across the gut-vascular barrier (GVB), which plays an essential role in intestinal immunity. Naringenin is reported to have therapeutic potential against several intestinal disorders. However, the effect of naringenin on GVB disruption has been rarely studied. This study aims to investigate the effect of naringenin on GVB function and the potential mechanism. In the present study, the in vitro GVB disruption of rat intestinal microvascular endothelial cells (RIMVEC) was induced by 50 ng mL-1 of tumor necrosis factor-α (TNF-α). The integrity of the in vitro GVB was determined by Evans blue (EB)-albumin efflux assay and trans-endothelial electrical resistance (TER). Meanwhile, the expression of tight junction proteins and the related NF-κB, MLCK/p-MLC and NLRP3 pathways were determined using enzyme-linked immunosorbent assay (ELISA), real-time quantitative polymerase chain reaction (RT-qPCR), western blot analysis and immunofluorescence. The results show that naringenin (100 µM) inhibits TNF-α-induced interleukin (IL)-6 hypersecretion, alleviates GVB disruption and mitigates the change in the tight junction protein expression pattern. Naringenin inhibits the GVB-disruption-associated activation of the MLCK/p-MLC system and TLR4/NF-κB/NLRP3 pathways. Furthermore, naringenin shows a similar effect to that of NF-κB inhibitor Bay 11-7082 in reducing the TNF-α-induced activation of NLRP3, p-MLC and secondary GVB disruption. The results suggest that naringenin evidently alleviates TNF-α-induced in vitro GVB disruption via the maintenance of a tight junction protein pattern, partly with the inhibition of the NF-κB-mediated MLCK/p-MLC and NLRP3 pathway activation.


Assuntos
Flavanonas/farmacologia , Mucosa Intestinal , Microvasos , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Animais , Células Cultivadas , Inflamassomos/efeitos dos fármacos , Inflamassomos/metabolismo , Mucosa Intestinal/irrigação sanguínea , Mucosa Intestinal/citologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Microvasos/citologia , Microvasos/efeitos dos fármacos , Microvasos/metabolismo , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas de Junções Íntimas/metabolismo
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