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1.
Bratisl Lek Listy ; 121(1): 73-78, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31950843

RESUMO

AIM: The aim of the present study was to investigate the immunohistochemical expression of selected collagen types, namely collagen types I and V and procollagen type III in the renal parenchyma and interstitium and in the myocardium of spontaneously hypertensive rats. MATERIAL AND METHODS: For the present study, we used two age groups of 6- and 12-month-old spontaneously hypertensive rats. An immunohistochemical analysis was conducted with monoclonal antibodies against collagen types I and V and procollagen type III. A semi-quantitative analysis of immunostaining intensity was conducted with the Image J software. RESULTS: In the kidney, all three molecules showed higher expression at the age of 12 months, which was particularly notable for procollagen type III and collagen type V, which stained as highly-positive. In the myocardium, the immunoreactivity of collagen types I and V was stronger in 12-month-old animals, while that of procollagen type III did not change substantially. CONCLUSION: The present study suggests a role of collagen types III and V in hypertensive kidney disease, while also establishing the role of increased expression of collagen types I and V in adverse myocardial remodeling (Tab. 1, Fig. 2, Ref. 48).


Assuntos
Hipertensão , Rim , Miocárdio , Animais , Colágeno/metabolismo , Coração , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Rim/metabolismo , Miocárdio/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Remodelação Vascular
2.
Medicine (Baltimore) ; 99(1): e18612, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31895813

RESUMO

BACKGROUND: Uterus transplantation is a complex, multi-step experimental procedure used for the treatment of uterus absence or uterus anomaly that prevents embryo implantation or pregnancy completion. METHOD: To date, only 51 uterus transplants worldwide had been performed. When simplified, it is vascularized composite allograft transplantation. While it is still an experimental procedure with encouraging results for the future, there are still many issues that have to be clarified. The most serious complications of uterus transplantation are graft rejection or grafts vascular failure. RESULTS: So far, no reference to the atherosclerotic arterial infiltration of the uterus arteries was suggested and studied as one of the main causes of graft's failure. CONCLUSION: In this review we summarized current knowledge and possible role of uterus arterial damage, including atherosclerotic changes on the graft's survival.


Assuntos
Aterosclerose/etiologia , Artéria Uterina , Útero/transplante , Alotransplante de Tecidos Compostos Vascularizados/efeitos adversos , Feminino , Humanos , Óxido Nítrico/metabolismo , Túnica Íntima/metabolismo , Útero/irrigação sanguínea , Remodelação Vascular
3.
Int Heart J ; 61(1): 160-168, 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-31956132

RESUMO

Pulmonary arterial hypertension (PAH) is a serious and fatal cardiovascular disorder characterized by increased pulmonary vascular resistance and progressive pulmonary vascular remodeling. The underlying pathological mechanisms of PAH are multi-factorial and multi-cellular. Alginate oligosaccharide (AOS), which is produced by depolymerizing alginate, shows better pharmacological activities and beneficial effects. The present study was undertaken to investigate the effects and potential mechanisms of AOS-mediated alleviation of pulmonary hypertension. Pulmonary hypertension was induced in Sprague-Dawley rats by a single intraperitoneal injection of monocrotaline (MCT; 60 mg/kg). Five weeks after the injection of MCT, AOS (5, 10, and 20 mg·kg-1·d-1) was injected intraperitoneally for another three weeks. The results showed that AOS prevented the development of MCT-induced pulmonary hypertension and right ventricular hypertrophy in a dose-dependent manner. AOS treatment also prevented MCT-induced pulmonary vascular remodeling via inhibition of the TGF-ß1/p-Smad2 signaling pathway. Furthermore, AOS treatment downregulated the expression of malondialdehyde, nicotinamide adenine dinucleotide phosphate oxidase, and pro-inflammatory cytokines, decreased macrophage infiltration, and upregulated the expression of anti-inflammatory cytokines. These findings indicate that AOS exerts anti-oxidative and anti-inflammatory effects in pulmonary arteries, which may contribute to the alleviation of pulmonary hypertension and pulmonary vascular remodeling.


Assuntos
Alginatos/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Antioxidantes/administração & dosagem , Hipertrofia Ventricular Direita/tratamento farmacológico , Monocrotalina/efeitos adversos , /tratamento farmacológico , Alginatos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hipertrofia Ventricular Direita/induzido quimicamente , Hipertrofia Ventricular Direita/metabolismo , Injeções Intraperitoneais , Masculino , Malondialdeído/metabolismo , /metabolismo , Distribuição Aleatória , Ratos , Remodelação Vascular/efeitos dos fármacos
4.
Am J Forensic Med Pathol ; 41(1): 1-4, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31977349

RESUMO

The popularity of e-cigarettes (vaping) has been on the rise in recent years, but the adverse effects of vaping have been greatly unknown. In 2019, the use of vaping products has been linked to an outbreak of severe lung disease, some cases of which have progressed to death. One death attributed to vaping is presented with emphasis on the gross and histopathological findings from the autopsy. These findings were correlated with the patient's clinical course and medicolegal investigation to determine the cause of death. To our knowledge, this is the first confirmed death in the United States that was directly attributed to the use of vaping.


Assuntos
Lesão Pulmonar Aguda/patologia , Sistemas Eletrônicos de Liberação de Nicotina , Pulmão/patologia , Síndrome do Desconforto Respiratório do Adulto/patologia , Vaping/efeitos adversos , Lesão Pulmonar Aguda/etiologia , Adulto , Canabinoides , Proliferação de Células , Pneumonia em Organização Criptogênica/diagnóstico , Feminino , Fibroblastos/patologia , Patologia Legal , Hemorragia/patologia , Humanos , Hipertensão , Hipertrofia Ventricular Esquerda/patologia , Macrófagos/patologia , Miocárdio/patologia , Obesidade Mórbida , Tamanho do Órgão , Óleos Vegetais , Alvéolos Pulmonares/patologia , Síndrome do Desconforto Respiratório do Adulto/etiologia , Estados Unidos , Remodelação Vascular
5.
Nat Rev Cardiol ; 17(1): 52-63, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31366922

RESUMO

Flowing blood generates a frictional force called shear stress that has major effects on vascular function. Branches and bends of arteries are exposed to complex blood flow patterns that exert low or low oscillatory shear stress, a mechanical environment that promotes vascular dysfunction and atherosclerosis. Conversely, physiologically high shear stress is protective. Endothelial cells are critical sensors of shear stress but the mechanisms by which they decode complex shear stress environments to regulate physiological and pathophysiological responses remain incompletely understood. Several laboratories have advanced this field by integrating specialized shear-stress models with systems biology approaches, including transcriptome, methylome and proteome profiling and functional screening platforms, for unbiased identification of novel mechanosensitive signalling pathways in arteries. In this Review, we describe these studies, which reveal that shear stress regulates diverse processes and demonstrate that multiple pathways classically known to be involved in embryonic development, such as BMP-TGFß, WNT, Notch, HIF1α, TWIST1 and HOX family genes, are regulated by shear stress in arteries in adults. We propose that mechanical activation of these pathways evolved to orchestrate vascular development but also drives atherosclerosis in low shear stress regions of adult arteries.


Assuntos
Aterosclerose/genética , Endotélio Vascular/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Mecanotransdução Celular/genética , Animais , Aterosclerose/metabolismo , Aterosclerose/fisiopatologia , Endotélio Vascular/fisiopatologia , Predisposição Genética para Doença , Humanos , Neovascularização Fisiológica/genética , Fenótipo , Fluxo Sanguíneo Regional , Fatores de Risco , Estresse Mecânico , Remodelação Vascular/genética
6.
Medicine (Baltimore) ; 98(50): e18241, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31852089

RESUMO

T helper 17 (Th17) cells are related to the progression of aortic dissection. This study aimed to determine whether circulating Th17 levels are associated with the prognosis of acute Stanford type B aortic dissection (STBAD) after thoracic endovascular aortic repair (TEVAR).A cohort study was performed and STBAD patients (n = 140) received TEVAR were enrolled, the circulating Th17 levels were measured and the patients were divided into low and high Th17 groups, and 36 months of follow-up was performed. The data for mortality, survival outcomes, heart structure and function changes, aortic regurgitation prevalence, and aortic remodeling outcomes were recorded.Lower mortality and fewer complications were observed in the low Th17 group than in the high Th17 group in the third year of follow-up. In addition, the low Th17 group exhibited better cardiac remodeling and cardiac function when compared with that in the high Th17 group in the second to third year after TEVAR. Aortic reflux was improved in both groups but was more pronounced in the low Th17 group. During follow-up, the true lumen of the proximal thoracic aorta at the level of the celiac trunk in both the low and high Th17 groups continuously enlarged and was more pronounced in the low Th17 group.Circulating Th17 cells were related to cardiac and aortic remodeling and prognosis during STBAD after TEVAR. Anti-inflammatory therapy may be useful for STBAD patients who have undergone TEVAR.


Assuntos
Aneurisma Dissecante/sangue , Aorta Torácica/cirurgia , Aneurisma da Aorta Torácica/sangue , Procedimentos Endovasculares/métodos , Células Th17/patologia , Remodelação Vascular , Doença Aguda , Adulto , Aneurisma Dissecante/diagnóstico , Aneurisma Dissecante/cirurgia , Aorta Torácica/diagnóstico por imagem , Aorta Torácica/fisiopatologia , Aneurisma da Aorta Torácica/diagnóstico , Aneurisma da Aorta Torácica/cirurgia , Angiografia por Tomografia Computadorizada , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Estudos Retrospectivos , Fatores de Tempo
7.
High Blood Press Cardiovasc Prev ; 26(5): 361-373, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31650516

RESUMO

High blood pressure (BP) is becoming a growing health issue even in children and adolescents. Moreover, BP elevation in youth frequently translates into children and adult hypertension contributing to the development of cardiovascular disease. The detection of early markers of vascular damage, potentially leading to overt cardiovascular disease, is important for clinical decisions about if and how to treat hypertension and can be useful in monitoring the effectiveness of the treatment. The purpose of this review is to summarize the actual knowledge about subclinical organ damage (SOD) in hypertensive children and adolescents and its association with cardiovascular disease in children and young adults. Our focus is especially put on left ventricular mass, pulse wave velocity, carotid intima-media thickness and microalbuminuria. We also want to address the scientific evidence about possible regression of SOD and cardiovascular risk with the use of behavioural and specific anti-hypertensive therapy. Indications from current guidelines are critically discussed.


Assuntos
Albuminúria/epidemiologia , Pressão Sanguínea , Cardiopatias/epidemiologia , Hipertensão/epidemiologia , Nefropatias/epidemiologia , Doenças Vasculares/epidemiologia , Adolescente , Fatores Etários , Albuminúria/diagnóstico , Albuminúria/fisiopatologia , Doenças Assintomáticas , Criança , Feminino , Cardiopatias/diagnóstico , Cardiopatias/fisiopatologia , Humanos , Hipertensão/diagnóstico , Hipertensão/fisiopatologia , Nefropatias/diagnóstico , Nefropatias/fisiopatologia , Masculino , Fatores de Risco , Doenças Vasculares/diagnóstico , Doenças Vasculares/fisiopatologia , Remodelação Vascular , Rigidez Vascular
8.
Medicine (Baltimore) ; 98(40): e17238, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31577715

RESUMO

INTRODUCTION: Arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis due to its higher patency and lower infection rate. However, its suboptimal maturation rate is a major weakness. Although substantial risk factors for AVF maturation failure have been disclosed, modifiable risk factors remain unknown. During the AVF maturation process, an elevated luminal pressure is required for outward remodeling; however, excessively high luminal pressure may also be detrimental to AVF maturation, which remains to be defined. We hypothesized that higher AVF luminal pressure is harmful to its maturation, and investigate its potential as a modifiable factor to improve AVF maturation. METHODS AND ANALYSIS: This prospective study includes patients undergoing surgical creation for a native AVF. The exclusion criteria were as follows: age <20 years, inability to sign an informed consent, and failure to create a native AVF due to technical difficulties. Demographic and laboratory profiles will be collected before AVF surgery. Vascular sonography will be performed within 1 week of AVF creation to measure the diameters, flow rates, and flow volumes of AVF and its branched veins. The pressure gradient within AVF will be estimated from the blood flow rates using the modified Bernoulli equation. The primary outcome is spontaneous AVF maturation defined as provision of sufficient blood flow for hemodialysis within 2 months of its creation without any interventional procedures. The secondary outcome is assisted AVF maturation, which is defined as AVF maturation within 2 months from its creation aided by any interventional procedure before the successful use of AVF. DISCUSSION: While contemporary theory for AVF maturation failure focuses on disturbed wall shear stress, complicate assumptions and measurement preclude its clinical applicability. AVF luminal pressure, which may be manipulated pharmaceutically and surgically, may be a target to improve the outcome of AVF maturation. TRIAL REGISTRATION: This study has been registered at the protocol registration and results system. The Protocol ID: NCT04017806.


Assuntos
Derivação Arteriovenosa Cirúrgica/métodos , Diálise Renal/métodos , Grau de Desobstrução Vascular/fisiologia , Remodelação Vascular/fisiologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Fumar Cigarros/epidemiologia , Comorbidade , Feminino , Hemodinâmica/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Insuficiência Renal/etiologia , Insuficiência Renal/terapia , Projetos de Pesquisa , Fatores de Risco , Fatores Sexuais , Taiwan , Fatores de Tempo , Adulto Jovem
9.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 50(3): 357-361, 2019 May.
Artigo em Chinês | MEDLINE | ID: mdl-31631603

RESUMO

Objectives: To assess morphological changes of distal aorta and the risk factors for adverse aortic remodeling inpost-TEVAR(thoracic endovascular aortic repair) patients with acute Stanford B aortic dissection. Methods: We retrospectively investigated the patients who underwent TEVAR for a type B dissection between October 2005 and December 2015. CT angiogram (CTA) was obtained for each patients preoperatively, postoperatively and during the post-operational follow-up. Based on Criadol partition principle, we divided the aorta into descending thoracic aorta area, suprarenal abdominal aorta area, infrarenal abdominal aorta area and iliac artery area, and evaluated the distribution of aortic tears and the form of true and false lumen in different aortic partition. Univariate and multivariate logistic regression analyses were used to analyze the risk factors affecting distal aortic remodeling. Results: Of 216 patients (mean follow-up (3.9±2.1) years) who were regularly followed up in our center, 47 patients (21.8%) occurred adverse remodeling in distal aorta. Univariate logistic regression indicated that abnormal aortic wall structure (Marfan's syndrome) and patent false lumen (existence of distal tears, decreased complete false lumen thrombosis) were associated with distal aortic adverse remodeling. Multivariate logistic regression showed that more tears in descending thoracic aorta area ( OR=1.36, 95% CI=1.12-1.58, P=0.005) and less tears in infrarenal abdominal aorta area ( OR=0.49, 95% CI=0.22-0.71, P<0.001) were independent risk factors affecting remodeling in distal aorta after TEVAR. Conclusions: Aortic wall structure abnormalities, a patent false lumen, more tears in descending thoracic aorta area, less tears in infrarenal abdominal aorta area are independent risk factors for adverse aortic remodeling in post-TEVAR patients with acute Stanford B aortic dissection.


Assuntos
Aneurisma Dissecante/patologia , Aneurisma da Aorta Torácica/patologia , Procedimentos Endovasculares , Remodelação Vascular , Aneurisma Dissecante/cirurgia , Aneurisma da Aorta Torácica/cirurgia , Humanos , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
10.
Vasc Health Risk Manag ; 15: 419-427, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31632046

RESUMO

Introduction: The increasing blood glucose level due to insulin resistance which occurs in diabetes mellitus (DM) may cause vascular damage. This study aims to prove the effect of the polysaccharide peptide (PsP) Ganoderma lucidum on improving vascular damage through an increase of circulating endothelial cells and circulating endothelial cells (CEC) ratio, decreased H2O2, triglyceride (TG), total cholesterol (TC) and insulin resistance in type 2 DM. Methods: Our study is a true experimental study with randomized posttest control group design that used 35 Wistar rats divided into five groups: normal, control (+) and three groups of different variant PsP doses 50, 150 and 300 mg/kg BW (n=7). Results: By using one-way ANOVA and post-hoc Duncan test, the results show a significant increase of endothelial progenitor cell (EPC) concentration (p=0.000) and ratio EPC:CEC (0.000) by dose-dependent fashion and also reduced CEC concentration (p=0.001), H2O2 (p=0.03), TG (p=0.001), TC (p=0.01) and insulin resistance (p=0.003). Conclusion: In this study, PsP induced endothelial repairing process and reduced the risk factor with 300 mg/kg BW as optimum dose. However, further research on EPC and CEC detection markers is important. Further research on PsP and clinical trial for commercial uses is also needed.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Angiopatias Diabéticas/prevenção & controle , Células Endoteliais/efeitos dos fármacos , Proteoglicanas/farmacologia , Reishi , Remodelação Vascular/efeitos dos fármacos , Animais , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/induzido quimicamente , Angiopatias Diabéticas/sangue , Angiopatias Diabéticas/induzido quimicamente , Angiopatias Diabéticas/patologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Peróxido de Hidrogênio/sangue , Resistência à Insulina , Lipídeos/sangue , Proteoglicanas/isolamento & purificação , Ratos Wistar , Reishi/química , Estreptozocina
11.
J Vasc Res ; 56(6): 284-295, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31574503

RESUMO

BACKGROUND: Arteries chronically constricted in culture remodel to smaller diameters. Conversely, elevated luminal shear stress (SS) promotes outward remodeling of arteries in vivo and prevents inward remodeling in culture in a nitric oxide synthase (NOS)-dependent manner. OBJECTIVES: To determine whether SS-induced prevention of inward remodeling in cultured arteries is specifically eNOS-dependent and requires dilation, and whether SS alters the expression of eNOS and other genes potentially involved in remodeling. METHODS: Female mouse thoracodorsal arteries were cannulated, pressurized to 80 mm Hg, and cultured for 2 days with low SS (<7 dyn/cm2), high SS (≥15 dyn/cm2), high SS + L-NAME (NOS inhibitor, 10-4 M), or high SS in arteries from eNOS-/- mice. In separate arteries cultured 1 day with low or high SS, eNOS and connexin (Cx) 37, Cx40, and Cx43 mRNA were assessed with real-time PCR. RESULTS: High SS caused little change in passive diameters after culture (-4.7 ± 2.0%), which was less than low SS (-18.9 ± 1.4%; p < 0.0001), high SS eNOS-/- (-18.0 ± 1.5; p < 0.001), or high SS + L-NAME (-12.0 ± 0.6%; nonsignificant) despite similar constriction during culture. Cx37 mRNA expression was increased (p < 0.05) with high SS, but other gene levels were not different. CONCLUSIONS: eNOS is involved in SS-induced prevention of inward remodeling in cultured small arteries. This effect does not require NO-mediated dilation. SS increased Cx37.


Assuntos
Artérias/metabolismo , Conexinas/metabolismo , Hemodinâmica , Mecanotransdução Celular , Óxido Nítrico Sintase Tipo III/metabolismo , Remodelação Vascular , Animais , Artérias/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Feminino , Mecanotransdução Celular/efeitos dos fármacos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Óxido Nítrico Sintase Tipo III/deficiência , Óxido Nítrico Sintase Tipo III/genética , Estresse Mecânico , Fatores de Tempo , Técnicas de Cultura de Tecidos , Remodelação Vascular/efeitos dos fármacos
12.
Presse Med ; 48(9): 919-930, 2019 Sep.
Artigo em Francês | MEDLINE | ID: mdl-31543394

RESUMO

Giant cell arteritis (GCA) is a large-vessel vasculitis involving the aorta and its main branches, especially supra aortic branches. Although much progress has been made, the pathophysiology remains incompletely understood. An initial trigger, suspected of infectious origin, lead to the maturation and recruitment of dendritic cells (DC). The lack of migration of these DC allows the local recruitment of T-lymphocytes (LT). These LT- CD4+ polarize in Type 1 helper (Th1), Th17 but also Th9. A qualitative and quantitative deficit in regulatory T cells (Treg) is observed under the influence of IL-21 overproduction. In addition, an imbalance in the Th17/Treg balance is favored by IL-6. The secretion of IFN-γ, IL-17, IL-6, IL-33 is responsible for a sustained local inflammatory reaction that is organized around tertiary lymphoid follicles. Locally recruited macrophages secrete reactive forms of oxygen together with VEGF and PDGF. These growth factors, together with neurotrophins and endothelin contribute to increase the proliferation of vascular smooth muscle cells (VSMCs). The imbalance between matrix metalloproteases (MMP)-2, MMP-9 and MMP-14 and tissue inhibitors of metalloproteases (TIMP)-1 and TIMP-2 also contribute to the remodeling process occurring in the vessel wall. Finally, arterial neovascularization contribute to the perpetuation of lymphocyte recruitment. This persistent remodeling is sometimes complicated by ischemic events responsible for the initial severity of the disease.


Assuntos
Arterite de Células Gigantes/fisiopatologia , Remodelação Vascular/fisiologia , Animais , Linfócitos B/fisiologia , Linfócitos T CD4-Positivos/fisiologia , Movimento Celular , Proliferação de Células , Células Dendríticas/fisiologia , Modelos Animais de Doenças , Predisposição Genética para Doença , Arterite de Células Gigantes/tratamento farmacológico , Arterite de Células Gigantes/etiologia , Arterite de Células Gigantes/patologia , Humanos , Interferon gama/metabolismo , Interleucina-17/metabolismo , Interleucina-33/metabolismo , Interleucina-6/fisiologia , Interleucinas/biossíntese , Ativação Linfocitária/fisiologia , Macrófagos/metabolismo , Metaloproteinases da Matriz/metabolismo , Músculo Liso Vascular/patologia , Neovascularização Patológica/fisiopatologia , Linfócitos T Reguladores/fisiologia , Células Th17/fisiologia
13.
Nat Commun ; 10(1): 4143, 2019 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-31515519

RESUMO

In pulmonary hypertension vascular remodeling leads to narrowing of distal pulmonary arterioles and increased pulmonary vascular resistance. Vascular remodeling is promoted by the survival and proliferation of pulmonary arterial vascular cells in a DNA-damaging, hostile microenvironment. Here we report that levels of Eyes Absent 3 (EYA3) are elevated in pulmonary arterial smooth muscle cells from patients with pulmonary arterial hypertension and that EYA3 tyrosine phosphatase activity promotes the survival of these cells under DNA-damaging conditions. Transgenic mice harboring an inactivating mutation in the EYA3 tyrosine phosphatase domain are significantly protected from vascular remodeling. Pharmacological inhibition of the EYA3 tyrosine phosphatase activity substantially reverses vascular remodeling in a rat model of angio-obliterative pulmonary hypertension. Together these observations establish EYA3 as a disease-modifying target whose function in the pathophysiology of pulmonary arterial hypertension can be targeted by available inhibitors.


Assuntos
Proteínas de Ligação a DNA/metabolismo , /fisiopatologia , Remodelação Vascular , Animais , Apoptose/efeitos dos fármacos , Benzobromarona/análogos & derivados , Benzobromarona/farmacologia , Cardiomegalia/complicações , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA , Reparo do DNA/efeitos dos fármacos , Proteínas de Ligação a DNA/antagonistas & inibidores , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/patologia , Hipóxia/complicações , Hipóxia/fisiopatologia , Masculino , Camundongos Transgênicos , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Artéria Pulmonar/patologia , Ratos Sprague-Dawley , Remodelação Vascular/efeitos dos fármacos
14.
Int J Mol Sci ; 20(18)2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31500245

RESUMO

Vascular remodeling and angiogenesis are required to improve the perfusion of ischemic tissues. The hypoxic environment, induced by ischemia, is a potent stimulus for hypoxia inducible factor 1α (HIF-1α) upregulation and activation, which induce pro-angiogenic gene expression. We previously showed that the tyrosine phosphatase SHP-2 drives hypoxia mediated HIF-1α upregulation via inhibition of the proteasomal pathway, resulting in revascularization of wounds in vivo. However, it is still unknown if SHP-2 mediates HIF-1α upregulation by affecting 26S proteasome activity and how the proteasome is regulated upon hypoxia. Using a reporter construct containing the oxygen-dependent degradation (ODD) domain of HIF-1α and a fluorogenic proteasome substrate in combination with SHP-2 mutant constructs, we show that SHP-2 inhibits the 26S proteasome activity in endothelial cells under hypoxic conditions in vitro via Src kinase/p38 mitogen-activated protein kinase (MAPK) signalling. Moreover, the simultaneous expression of constitutively active SHP-2 (E76A) and inactive SHP-2 (CS) in separate hypoxic wounds in the mice dorsal skin fold chamber by localized magnetic nanoparticle-assisted lentiviral transduction showed specific regulation of proteasome activity in vivo. Thus, we identified a new additional mechanism of SHP-2 mediated HIF-1α upregulation and proteasome activity, being functionally important for revascularization of wounds in vivo. SHP-2 may therefore constitute a potential novel therapeutic target for the induction of angiogenesis in ischemic vascular disease.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/química , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Pele/lesões , Animais , Hipóxia Celular , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Sistema de Sinalização das MAP Quinases , Nanopartículas de Magnetita , Masculino , Camundongos , Mutação , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Proteólise , Pele/irrigação sanguínea , Remodelação Vascular
15.
Biochemistry (Mosc) ; 84(7): 762-772, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31509727

RESUMO

Intravasation is a key step in cancer metastasis during which tumor cells penetrate the vessel wall and enter circulation, thereby becoming circulating tumor cells and potential metastatic seeds. Understanding the molecular mechanisms of intravasation is critically important for the development of therapeutic strategies to prevent metastasis. In this article, we review current data on the mechanisms of cancer cell intravasation into the blood and lymphatic vessels. The entry of mature thymocytes into the circulation and of dendritic cells into the regional lymph nodes is considered as example of intravasation under physiologically normal conditions. Intravasation in a pathophysiological state is illustrated by the reverse transendothelial migration of leukocytes into the bloodstream from the sites of inflammation mediated by the sphingosine 1-phosphate interaction with its receptors. Intravasation involves both invasion-dependent and independent mechanisms. In particular, mesenchymal and amoeboid cell invasion, as well as neoangiogenesis and vascular remodeling, are discussed to play a significant role in the entry of tumor cells to the circulation. Special attention is given to the contribution of macrophages to the intravasation via the CSF1/EGF (colony stimulating factor 1/epidermal growth factor) paracrine signaling pathway and the TMEM (tumor microenvironment of metastasis)-mediated mechanisms. Other mechanisms including intravasation of tumor cell clusters surrounded by the vessel wall elements, cooperative intravasation (entry of non-invasive tumor cells to the circulation following invasive tumor cells), and intravasation associated with the vasculogenic mimicry (formation of vascular channels by tumor cells) are also discussed. Novel intravasation-specific mechanisms that have not yet been described in the literature are suggested. The importance of targeted therapeutic strategies to prevent cancer intravasation is emphasized.


Assuntos
Invasividade Neoplásica/fisiopatologia , Metástase Neoplásica/fisiopatologia , Migração Transendotelial e Transepitelial , Microambiente Tumoral , Permeabilidade Capilar , Fator de Crescimento Epidérmico/metabolismo , Humanos , Fator Estimulador de Colônias de Macrófagos/metabolismo , Macrófagos/metabolismo , Comunicação Parácrina , Remodelação Vascular
16.
Int J Mol Sci ; 20(18)2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31487864

RESUMO

Patients with chronic obstructive pulmonary disease (COPD) show systemic consequences, such as chronic systemic inflammation leading to changes in the airway, airway penetrability, and endothelial function. Endothelial dysfunction is characterized by a list of alterations of endothelium towards reduced vasodilation, proinflammatory state, detachment and apoptosis of endothelial cells, and development of atherosclerosis. COPD-induced endothelial dysfunction is associated with elevated cardiovascular risk. The increment of physical activities such as pulmonary rehabilitation (PR) training have a significant effect on COPD, thus, PR can be an integrative part of COPD treatment. In this narrative review the focus is on the function of endothelial inflammatory mediators [cytokines, chemokines, and cellular proteases] and pulmonary endothelial cells and endothelial dysfunction in COPD as well as the effects of dysfunction of the endothelium may play in COPD-related pulmonary hypertension. The relationship between smoking and endothelial dysfunction is also discussed. The connection between different pulmonary rehabilitation programs, arterial stiffness and pulse wave velocity (PWV) is presented. Endothelial dysfunction is a significant prognostic factor of COPD, which can be characterized by PWV. We discuss future considerations, like training programs, as an important part of the treatment that has a favorable impact on the endothelial function.


Assuntos
Endotélio Vascular/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Apoptose , Endotélio Vascular/patologia , Humanos , Doença Pulmonar Obstrutiva Crônica/patologia , Doença Pulmonar Obstrutiva Crônica/terapia , Remodelação Vascular , Rigidez Vascular
17.
Int J Mol Sci ; 20(16)2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31398927

RESUMO

Atrial natriuretic peptide (ANP) is a cardiac hormone belonging to the family of natriuretic peptides (NPs). ANP exerts diuretic, natriuretic, and vasodilatory effects that contribute to maintain water-salt balance and regulate blood pressure. Besides these systemic properties, ANP displays important pleiotropic effects in the heart and in the vascular system that are independent of blood pressure regulation. These functions occur through autocrine and paracrine mechanisms. Previous works examining the cardiac phenotype of loss-of-function mouse models of ANP signaling showed that both mice with gene deletion of ANP or its receptor natriuretic peptide receptor A (NPR-A) developed cardiac hypertrophy and dysfunction in response to pressure overload and chronic ischemic remodeling. Conversely, ANP administration has been shown to improve cardiac function in response to remodeling and reduces ischemia-reperfusion (I/R) injury. ANP also acts as a pro-angiogenetic, anti-inflammatory, and anti-atherosclerotic factor in the vascular system. Pleiotropic effects regarding brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) were also reported. In this review, we discuss the current evidence underlying the pleiotropic effects of NPs, underlying their importance in cardiovascular homeostasis.


Assuntos
Sistema Cardiovascular/metabolismo , Peptídeos Natriuréticos/metabolismo , Animais , Sistema Cardiovascular/efeitos dos fármacos , Humanos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Peptídeo Natriurético Encefálico/metabolismo , Peptídeo Natriurético Encefálico/farmacologia , Peptídeos Natriuréticos/farmacologia , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Remodelação Vascular/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
18.
BMC Bioinformatics ; 20(1): 442, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31455206

RESUMO

BACKGROUND: Contemporary biological observations have revealed a large variety of mechanisms acting during the expansion of a tumor. However, there are still many qualitative and quantitative aspects of the phenomenon that remain largely unknown. In this context, mathematical and computational modeling appears as an invaluable tool providing the means for conducting in silico experiments, which are cheaper and less tedious than real laboratory experiments. RESULTS: This paper aims at developing an extensible and computationally efficient framework for in silico modeling of tumor growth in a 3-dimensional, inhomogeneous and time-varying chemical environment. The resulting model consists of a set of mathematically derived and algorithmically defined operators, each one addressing the effects of a particular biological mechanism on the state of the system. These operators may be extended or re-adjusted, in case a different set of starting assumptions or a different simulation scenario needs to be considered. CONCLUSION: In silico modeling provides an alternative means for testing hypotheses and simulating scenarios for which exact biological knowledge remains elusive. However, finer tuning of pertinent methods presupposes qualitative and quantitative enrichment of available biological evidence. Validation in a strict sense would further require comprehensive, case-specific simulations and detailed comparisons with biomedical observations.


Assuntos
Modelos Biológicos , Modelos Teóricos , Neoplasias/patologia , Algoritmos , Proliferação de Células , Simulação por Computador , Difusão , Glucose/metabolismo , Glicólise , Humanos , Necrose , Neoplasias/irrigação sanguínea , Neovascularização Patológica/patologia , Oxigênio/metabolismo , Fatores de Tempo , Remodelação Vascular
19.
Artigo em Chinês | MEDLINE | ID: mdl-31434374

RESUMO

Objective: To investigate blood pressure and vascular remodeling of OSAS by establishing the chronic-intermittent hypoxia model in rat. Methods: Experiments were performed on 35 adult male Sprague-Dawley rats. Animals were randomly divided into four groups: unhandled control group (with 5 rats in it), CIH group at 9/6/3 weeks (with 10 ratsin each group). Rats in CIH group went through 8-hour intermittent hypoxia everyday, and those in control group were raising normally. After 9-week experiment, blood pressure was measured. The changes of the following indexes were observed: pathological changes of aorta and the middle aorta thickness (HE staining), the collagen of aorta wall (Masson staining). The experimental data were analyzed by SPSS 24.0 statistical software. The variance was analyzed by one-way analysis of variance, and the irregularity was selected using the calibration t test. Results: The systolic and diastolic blood pressures of the CIH9, 6, and 3 weeks groups and the control group were: (127±13) and (79±9), (124±11) and (81±7), (101±11) and (75±9), (91±10) and (65±9) mmHg (1 mmHg=0.133 kPa). The systolic blood pressure and diastolic blood pressure of the rats in the week of CIH 9 and 6 weeks were significantly higher than the control group (F=14.64, P=0.000; F=6.81, P=0.000). There was no significant difference in the mean blood pressure between the three groups of CIH and the control group. Membrane thickness in CIH9, 6 and 3 weeks and control group were: (20±2), (19±2), (14±2), (13±3) µm. Compared with the control group, the aortic pathology and thickness of the middle layer of the CIH9 and 6 weeks group were significantly thicker (F=20.24, P=0.000), but there was no significant difference between the CIH3 week group and the control group; the collagen deposition was unchanged compared with the control group. Conclusion: Intermittent hypoxia for 6 weeks or more in rats resulted in the increasement of blood pressure, morphological changes of aorta and vascular remodeling in thickened media.


Assuntos
Aorta Torácica/fisiopatologia , Pressão Sanguínea/fisiologia , Hipóxia/fisiopatologia , Remodelação Vascular/fisiologia , Animais , Doença Crônica , Modelos Animais de Doenças , Hipóxia/complicações , Masculino , Ratos , Ratos Sprague-Dawley
20.
Graefes Arch Clin Exp Ophthalmol ; 257(10): 2179-2184, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31451908

RESUMO

PURPOSE: Netrin-4 (NTN4) is a protein that plays an important role in the regulation of angiogenesis in the pathological retina. Some evidences show that it can also have a role in inflammation and vascular stability. We will explore these questions in vivo in the mature mouse retina. METHODS: We created a NTN4 knockout that expresses EGFP in mononuclear phagocytes (CSFR1-positive cells) to track inflammation in vivo in the retina by scanning laser ophthalmoscopy (SLO). Fundus angiography permitted to study blood vessels. Retinal function was assessed with electroretinography (ERG). RESULTS: Lack of NTN4 leads to an increased amount of amoeboid mononuclear phagocytes in the adult retina, and blood vessels displayed increased tortuosity when compared with the wildtype. Inner retina function also seemed affected in NTN4 null. Lack of NTN4 resulted in a higher persistence of hyaloid artery and spontaneous leakage in the adult retina. No differences were found regarding vessel bifurcation, vessel width, or vein/artery ratio. CONCLUSIONS: These in vivo data show for the first time that lack of NTN4 induces changes in the retinal vascular phenotype in a non-pathological scenario. This evidence widens the role of NTN4 as a guidance cue in vascular remodeling.


Assuntos
Netrinas/metabolismo , Neovascularização Retiniana/metabolismo , Vasos Retinianos/metabolismo , Remodelação Vascular/fisiologia , Animais , Biomarcadores/metabolismo , Modelos Animais de Doenças , Eletrorretinografia , Angiofluoresceinografia , Fundo de Olho , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oftalmoscopia , Neovascularização Retiniana/patologia , Neovascularização Retiniana/fisiopatologia , Vasos Retinianos/patologia , Vasos Retinianos/fisiopatologia
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