Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.432
Filtrar
1.
Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi ; 34(11): 1429-1437, 2020 Nov 15.
Artigo em Chinês | MEDLINE | ID: mdl-33191702

RESUMO

Objective: To study the local vascular remodeling, inflammatory response, and their correlations following acute spinal cord injury (SCI) with different grades, and to assess the histological changes in SCI rats. Methods: One hundred and sixteen adult female Sprague Dawley rats were randomly divided into 4 groups ( n=29). The rats in sham group were received laminectomy only. A standard MASCIS spinal cord compactor was applied with drop height of 12.5, 25.0, or 50.0 mm to establish the mild, moderate, or severe SCI model, respectively. Quantitative rat endothelial cell antigen 1 (RECA1) and CD68 positive areas and the correlations were studied by double immunofluorescent (DIF) staining at 12 hours, 24 hours, 3 days, 7 days, and 28 days following SCI. Moreover, qualitative neurofilament-H (NF-H) and glial fibrillary acidic protein (GFAP) positive glial cells were studied by DIF staining at 28 days. ELISA was used to detect the levels of tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß), and IL-6 in spinal cord homogenates at 12 hours, 24 hours, and 3 days, and the correlations between TNF-α, IL-1ß, or IL-6 levels and microvascular density (RECA1) were accordingly studied. Moreover, the neural tissue integrity and neuron damage were assessed by HE staining at 12 hours, 24 hours, 3 days, 7 days, and 28 days, and Nissl's staining at 28 days following SCI, respectively. Results: DIF staining revealed that the ratio of RECA1 positive area was the highest in moderate group, higher in mild and severe groups, and the lowest in sham group with significant differences between groups ( P<0.05). The ratio of CD68 positive area was the highest in severe group, higher in moderate and mild groups, and the lowest in sham group with significant differences between groups ( P<0.05), except the comparisons between mild and moderate groups at 24 hours and 28 days after SCI ( P>0.05). There was no significant correlation between the RECA1 and CD68 expressions in sham group at different time points ( P>0.05). At 12 and 24 hours after SCI, the RECA1 and CD68 expressions in mild and moderate groups showed significant positive correlations ( P<0.05), while no significant correlation was found in severe group ( P>0.05). No significant correlations between the RECA1 and CD68 expressions was shown in all SCI groups at 3 days and in severe group at 7 days ( P>0.05), while the negative correlations were shown in mild and moderate groups at 7 days, and in all SCI groups at 28 days ( P<0.05). In mild, moderate, and severe groups, the axons became disrupted, shorter and thicker rods-like, or even merged blocks with increased injury, while the astrocytes decreased in number, unorganized and condensed in appearance. ELISA studies showed that TNF-α, IL-1ß, and IL-6 levels in sham group were significantly lower than those in other 3 groups at different time points ( P>0.05). The differences in TNF-α, IL-1ß, and IL-6 levels between SCI groups at different time points were sinificant ( P<0.05), except IL-1ß levels between the mild and moderate groups at 12 hours ( P>0.05). Three inflammatory factors were all significantly correlated with the microvascular density grades ( P<0.05). Histological analysis indicated that the damage to spinal cord tissue structure correlated with the extent of SCI. In severe group, local hemorrhage, edema, and infiltration of inflammatory cells were found the most drastic, the grey/white matter boundary was disappeared concurrently with the formation of cavity and shortage of normal neurons. Conclusion: In the acute stage following mild or moderate SCI, progressively aggravated injury result in higher microvessel density and increased inflammation. However, at the SCI region, the relation between microvessel density and inflammation inverse with time in the different grades of SCI. Accordingly, the destruction of neural structures positively relate to the grades of SCI and severity of inflammation.


Assuntos
Traumatismos da Medula Espinal , Remodelação Vascular , Animais , Feminino , Ratos , Ratos Sprague-Dawley , Medula Espinal , Fator de Necrose Tumoral alfa
2.
J Pharmacol Sci ; 144(4): 237-244, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33070843

RESUMO

Hypoxic pulmonary hypertension (HPH) is a progressive and irreversible disease that reduces survival. Echinacoside is a phenylethanoid glycoside from Tibetan herbs known for its vasorelaxant effect and for inhibiting the proliferation of rat pulmonary arterial smooth muscle cells. This study aimed to investigate the effect of echinacoside on HPH. Sprague Dawley rats were housed in a hypobaric hypoxia chamber (4500 m) for 28 days to obtain the HPH model. Echinacoside (3.75, 7.5, 15, 30 and 40 mg/kg) was administered by intraperitoneal injection from the 1st to the 28th day. The mean pulmonary artery pressure (mPAP), right ventricular hypertrophy index, hemoglobin, hematocrit, red blood cell concentration and morphological change of pulmonary arteries were evaluated. Vascular perfusion assay was used to assess the pulmonary artery function. Echinacoside reduced mPAP, hemoglobin, hematocrit, right ventricular hypertrophy index and mean wall thickness% of pulmonary arteries in HPH rats. It significantly increased maximum vasoconstriction percentage of pulmonary arteries induced by noradrenaline in a dose-dependent manner. In addition, it improved the responsiveness of pulmonary arteries to acetylcholine and sodium nitroprusside. Therefore, Echinacoside might be an effective treatment against HPH, since it regulated pulmonary artery endothelium and smooth muscle layer function and improved the remodeling of pulmonary artery.


Assuntos
Glicosídeos/administração & dosagem , Glicosídeos/farmacologia , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/etiologia , Hipóxia/complicações , Fitoterapia , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/fisiopatologia , Remodelação Vascular/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Glicosídeos/uso terapêutico , Hipertensão Pulmonar/fisiopatologia , Hipertensão Pulmonar/prevenção & controle , Técnicas In Vitro , Injeções Intraperitoneais , Masculino , Ratos Sprague-Dawley , Vasodilatadores
3.
Sheng Li Xue Bao ; 72(5): 541-550, 2020 Oct 25.
Artigo em Chinês | MEDLINE | ID: mdl-33106824

RESUMO

The occurrence and development of pulmonary arterial hypertension (PAH) is closely related to the genetic mutation of bone morphogenetic protein receptor type II (BMPRII) encoding gene and the inflammatory response mediated by nuclear factor κB (NF-κB) pathway. This paper was aimed to investigate the effect of NF-κB pathway inhibitors on lipopolysaccharide (LPS)-induced pulmonary artery endothelial cell injury. Human pulmonary artery endothelial cells were treated with 1 µg/mL of LPS. The expression levels of BMPRII and interleukin-8 (IL-8) were detected by Western blot and qPCR. The rat PAH model was established by intraperitoneal (i.p.) injection of monocrotaline (MCT). The expression levels of BMPRII and IL-8 in pulmonary artery endothelial cells were detected by immunofluorescence staining. Cardiac hemodynamic changes and pulmonary vascular remodeling were detected in the MCT-PAH model rats. The results showed that LPS caused down-regulation of BMPRII expression and up-regulation of IL-8 expression in human pulmonary artery endothelial cells. NF-κB inhibitor BAY11-7082 (10 µmol/L) reversed the effect of LPS. In the pulmonary artery endothelial cells of MCT-PAH model, BMPRII expression was down-regulated, IL-8 expression was up-regulated, weight ratio of right ventricle to left ventricle plus septum [RV/(LV+S)] and right ventricular systolic pressure (RVSP) were significantly increased, cardiac output (CO) and tricuspid annular plane systolic excursion (TAPSE) were significantly reduced, and pulmonary vessel wall was significantly thickened. BAY11-7082 (5 mg/kg, i.p., 21 consecutive days) reversed the above changes in the MCT-PAH model rats. These results suggest that LPS down-regulates the expression level of BMPRII through NF-κB signaling pathway, promoting the occurrence and development of PAH. Therefore, the NF-κB pathway can be used as a potential therapeutic target for PAH.


Assuntos
Receptores de Proteínas Morfogenéticas Ósseas Tipo II , Hipertensão Pulmonar , Animais , Regulação para Baixo , Células Endoteliais/metabolismo , Humanos , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/tratamento farmacológico , Lipopolissacarídeos , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley , Remodelação Vascular
4.
PLoS One ; 15(10): e0239561, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33091038

RESUMO

Pulmonary hypertension and cor pulmonale are complications of severe equine asthma, as a consequence of pulmonary hypoxic vasoconstriction. However, as pulmonary hypertension is only partially reversible by oxygen administration, other etiological factors are likely involved. In human chronic obstructive pulmonary disease, pulmonary artery remodeling contributes to the development of pulmonary hypertension. In rodent models, pulmonary vascular remodeling is present as a consequence of allergic airway inflammation. The present study investigated the presence of remodeling of the pulmonary arteries in severe equine asthma, its distribution throughout the lungs, and its reversibility following long-term antigen avoidance strategies and inhaled corticosteroid administration. Using histomorphometry, the total wall area of pulmonary arteries from different regions of the lungs of asthmatic horses and controls was measured. The smooth muscle mass of pulmonary arteries was also estimated on lung sections stained for α-smooth muscle actin. Reversibility of vascular changes in asthmatic horses was assessed after 1 year of antigen avoidance alone or treatment with inhaled fluticasone. Pulmonary arteries showed increased wall area in apical and caudodorsal lung regions of asthmatic horses in both exacerbation and remission. The pulmonary arteries smooth muscle mass was similarly increased. Both treatments reversed the increase in wall area. However, a trend for normalization of the vascular smooth muscle mass was observed only after treatment with antigen avoidance, but not with fluticasone. In conclusion, severe equine asthma is associated with remodeling of the pulmonary arteries consisting in an increased smooth muscle mass. The resulting narrowing of the artery lumen could enhance hypoxic vasoconstriction, contributing to pulmonary hypertension. In our study population, the antigen avoidance strategy appeared more promising than inhaled corticosteroids in controlling vascular remodeling. However, further studies are needed to support the reversibility of vascular smooth muscle mass remodeling after asthma treatment.


Assuntos
Asma/patologia , Asma/fisiopatologia , Artéria Pulmonar/patologia , Artéria Pulmonar/fisiopatologia , Remodelação Vascular , Animais , Cavalos
5.
Nat Commun ; 11(1): 5319, 2020 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-33087700

RESUMO

Arterial networks enlarge in response to increase in tissue metabolism to facilitate flow and nutrient delivery. Typically, the transition of a growing artery with a small diameter into a large caliber artery with a sizeable diameter occurs upon the blood flow driven change in number and shape of endothelial cells lining the arterial lumen. Here, using zebrafish embryos and endothelial cell models, we describe an alternative, flow independent model, involving enlargement of arterial endothelial cells, which results in the formation of large diameter arteries. Endothelial enlargement requires the GEF1 domain of the guanine nucleotide exchange factor Trio and activation of Rho-GTPases Rac1 and RhoG in the cell periphery, inducing F-actin cytoskeleton remodeling, myosin based tension at junction regions and focal adhesions. Activation of Trio in developing arteries in vivo involves precise titration of the Vegf signaling strength in the arterial wall, which is controlled by the soluble Vegf receptor Flt1.


Assuntos
Células Endoteliais/citologia , Células Endoteliais/fisiologia , Fatores de Troca do Nucleotídeo Guanina/fisiologia , Fator A de Crescimento do Endotélio Vascular/fisiologia , Remodelação Vascular/fisiologia , Animais , Animais Geneticamente Modificados , Tamanho Celular , Células Cultivadas , Fatores de Troca do Nucleotídeo Guanina/genética , Células Endoteliais da Veia Umbilical Humana , Humanos , Modelos Cardiovasculares , Fator de Crescimento Placentário/genética , Fator de Crescimento Placentário/fisiologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/fisiologia , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/fisiologia , Remodelação Vascular/genética , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Peixe-Zebra/fisiologia , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/fisiologia , Proteínas rac1 de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP/fisiologia
6.
PLoS One ; 15(9): e0235824, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32881898

RESUMO

Pulmonary hypertension due to left heart disease (PH-LHD) is a momentous pulmonary hypertension disease, and left heart disease is the most familiar cause. Mechanical stretching may be a crucial cause of vascular remodeling. While, the underlining mechanism of mechanical stretching-induced in remodeling of pulmonary vein in the early stage of PH-LHD has not been completely elucidated. In our study, the PH-LHD model rats were successfully constructed. After 25 days, doppler echocardiography and hemodynamic examination were performed. In addition, after treatment, the levels of matrix metalloproteinase-9 (MMP-9) and transforming growth factor-ß1 (TGF-ß1) were determined by ELISA, immunohistochemistry and western blot assays in the pulmonary veins. Moreover, the pathological change of pulmonary tissues was evaluated by H&E staining. Our results uncovered that left ventricular insufficiency and interventricular septal shift could be observed in PH-LHD model rats, and the right ventricular systolic pressure (RVSP) and mean left atrial pressure (mLAP) were also elevated in PH-LHD model rats. Meanwhile, we found that MMP-9 and TGF-ß1 could be highly expressed in PH-LHD model rats. Besides, we revealed that stretch-activated channel (SAC)/mitogen-activated protein kinases (MAPKs) signaling pathway could be involved in the upregulations of MMP-9 and TGF-ß1 mediated by mechanical stretching in pulmonary vein. Therefore, current research revealed that mechanical stretching induced the increasing expressions of MMP-9 and TGF-ß1 in pulmonary vein, which could be mediated by activation of SAC/MAPKs signaling pathway in the early stage of PH-LHD.


Assuntos
Hipertensão Pulmonar/fisiopatologia , Sistema de Sinalização das MAP Quinases , Metaloproteinase 9 da Matriz/metabolismo , Veias Pulmonares/fisiopatologia , Fator de Crescimento Transformador beta1/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia , Animais , Fenômenos Biomecânicos , Modelos Animais de Doenças , Ativação Enzimática , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/metabolismo , Masculino , Veias Pulmonares/metabolismo , Ratos , Ratos Sprague-Dawley , Estresse Mecânico , Remodelação Vascular , Disfunção Ventricular Esquerda/complicações , Disfunção Ventricular Esquerda/metabolismo
8.
Life Sci ; 259: 118253, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32795536

RESUMO

AIMS: We recently demonstrated that mechanical stretch increases the proliferation and apoptosis of vascular smooth muscle cells (VSMCs) by activating the protein disulfide isomerase (PDI) redox system, thus accelerating atherosclerotic lesion formation in the transplanted vein. At present, there are no efficient intervention measures to prevent this phenomenon. Berberine inhibits pathological vascular remodeling caused by hypertension, but the underlying mechanism is controversial. Herein, we investigate the role of berberine and the underlying mechanism of its effects on mechanical stretch-induced VSMC proliferation and apoptosis. MAIN METHODS: Mouse VSMCs cultivated on flexible membranes were pretreated for 1 h with one of the following substances: berberine, PDI inhibitor bacitracin, MAPK inhibitors, or ERS inhibitor 4-PBA. VSMCs were then subjected to mechanical stretch. Immunofluorescence and western blot were used to detect proliferation and apoptosis, as well as to analyze signaling pathways in VSMCs. KEY FINDINGS: Our results showed that berberine inhibits the PDI-endoplasmic reticulum stress system, thereby attenuating the simultaneous increase of VSMC proliferation and apoptosis in response to mechanical stretch. Interestingly, MAPK inhibitors PD98059, SP600125, and SB202190 significantly reduced the activation of ERS signaling cascades, and their combination with berberine had additive effects. The ERS inhibitor 4-PBA reduced PDI activation and ERS signaling, but not MAPK phosphorylation. Moreover, caspase-3 and caspase-12 were downregulated by berberine. SIGNIFICANCE: These results illustrate a novel mechanism of action of berberine that has practical implications. Our data provide important insights for the prevention and treatment of vascular remodeling and diseases caused by mechanical stretching during hypertension.


Assuntos
Berberina/farmacologia , Músculo Liso Vascular/metabolismo , Isomerases de Dissulfetos de Proteínas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Aterosclerose/metabolismo , Berberina/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , China , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Masculino , Fenômenos Mecânicos , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Oxirredução/efeitos dos fármacos , Fosforilação , Transdução de Sinais/efeitos dos fármacos , Estresse Mecânico , Remodelação Vascular
9.
Am J Physiol Heart Circ Physiol ; 319(3): H661-H681, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32762557

RESUMO

Preeclampsia is a major complication of pregnancy manifested as hypertension and often intrauterine growth restriction, but the underlying pathophysiological mechanisms are unclear. Predisposing genetic and environmental factors cause placental maladaptations leading to defective placentation, apoptosis of invasive cytotrophoblasts, inadequate expansive remodeling of the spiral arteries, reduced uteroplacental perfusion pressure, and placental ischemia. Placental ischemia promotes the release of bioactive factors into the maternal circulation, causing an imbalance between antiangiogenic soluble fms-like tyrosine kinase-1 and soluble endoglin and proangiogenic vascular endothelial growth factor, placental growth factor, and transforming growth factor-ß. Placental ischemia also stimulates the release of proinflammatory cytokines, hypoxia-inducible factor, reactive oxygen species, and angiotensin type 1 receptor agonistic autoantibodies. These circulating factors target the vascular endothelium, causing generalized endotheliosis in systemic, renal, cerebral, and hepatic vessels, leading to decreases in endothelium-derived vasodilators such as nitric oxide, prostacyclin, and hyperpolarization factor and increases in vasoconstrictors such as endothelin-1 and thromboxane A2. The bioactive factors also target vascular smooth muscle and enhance the mechanisms of vascular contraction, including cytosolic Ca2+, protein kinase C, and Rho-kinase. The bioactive factors could also target matrix metalloproteinases and the extracellular matrix, causing inadequate vascular remodeling, increased arterial stiffening, and further increases in vascular resistance and hypertension. As therapeutic options are limited, understanding the underlying vascular mechanisms and molecular targets should help design new tools for the detection and management of hypertension in pregnancy and preeclampsia.


Assuntos
Pressão Arterial , Hipertensão Induzida pela Gravidez/metabolismo , Placenta/irrigação sanguínea , Pré-Eclâmpsia/metabolismo , Artéria Uterina/metabolismo , Animais , Feminino , Humanos , Hipertensão Induzida pela Gravidez/etiologia , Hipertensão Induzida pela Gravidez/fisiopatologia , Hipóxia/metabolismo , Hipóxia/fisiopatologia , Isquemia/metabolismo , Isquemia/fisiopatologia , Placentação , Pré-Eclâmpsia/etiologia , Pré-Eclâmpsia/fisiopatologia , Gravidez , Fatores de Risco , Transdução de Sinais , Artéria Uterina/fisiopatologia , Remodelação Vascular , Rigidez Vascular
10.
Arterioscler Thromb Vasc Biol ; 40(10): 2494-2507, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32787523

RESUMO

OBJECTIVE: Currently, there are no approved drugs for abdominal aortic aneurysm (AAA) treatment, likely due to limited understanding of the primary molecular mechanisms underlying AAA development and progression. BAF60a-a unique subunit of the SWI/SNF (switch/sucrose nonfermentable) chromatin remodeling complex-is a novel regulator of metabolic homeostasis, yet little is known about its function in the vasculature and pathogenesis of AAA. In this study, we sought to investigate the role and underlying mechanisms of vascular smooth muscle cell (VSMC)-specific BAF60a in AAA formation. Approach and Results: BAF60a is upregulated in human and experimental murine AAA lesions. In vivo studies revealed that VSMC-specific knockout of BAF60a protected mice from both Ang II (angiotensin II)-induced and elastase-induced AAA formation with significant suppression of vascular inflammation, monocyte infiltration, and elastin fragmentation. Through RNA sequencing and pathway analysis, we found that the expression of inflammatory response genes in cultured human aortic smooth muscle cells was significantly downregulated by small interfering RNA-mediated BAF60a knockdown while upregulated upon adenovirus-mediated BAF60a overexpression. BAF60a regulates VSMC inflammation by recruiting BRG1 (Brahma-related gene-1)-a catalytic subunit of the SWI/SNF complex-to the promoter region of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) target genes. Furthermore, loss of BAF60a in VSMCs prevented the upregulation of the proteolytic enzyme cysteine protease CTSS (cathepsin S), thus ameliorating ECM (extracellular matrix) degradation within the vascular wall in AAA. CONCLUSIONS: Our study demonstrated that BAF60a is required to recruit the SWI/SNF complex to facilitate the epigenetic regulation of VSMC inflammation, which may serve as a potential therapeutic target in preventing and treating AAA.


Assuntos
Aneurisma da Aorta Abdominal/prevenção & controle , Aortite/prevenção & controle , Proteínas Cromossômicas não Histona/deficiência , Matriz Extracelular/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Remodelação Vascular , Animais , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Aortite/genética , Aortite/metabolismo , Aortite/patologia , Estudos de Casos e Controles , Catepsinas/metabolismo , Células Cultivadas , Proteínas Cromossômicas não Histona/genética , Modelos Animais de Doenças , Matriz Extracelular/patologia , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Transdução de Sinais
11.
Am J Physiol Renal Physiol ; 319(4): F624-F635, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32830539

RESUMO

Recently, we reported a mutation in γ-adducin (ADD3) was associated with an impaired myogenic response of the afferent arteriole and hypertension-induced chronic kidney disease (CKD) in fawn hooded hypertensive (FHH) rats. However, the mechanisms by which altered renal blood flow (RBF) autoregulation promotes hypertension-induced renal injury remain to be determined. The present study compared the time course of changes in renal hemodynamics and the progression of CKD during the development of DOCA-salt hypertension in FHH 1BN congenic rats [wild-type (WT)] with an intact myogenic response versus FHH 1BN Add3KO (Add3KO) rats, which have impaired myogenic response. RBF was well autoregulated in WT rats but not in Add3KO rats. Glomerular capillary pressure rose by 6 versus 14 mmHg in WT versus Add3KO rats when blood pressure increased from 100 to 150 mmHg. After 1 wk of hypertension, glomerular filtration rate increased by 38% and glomerular nephrin expression decreased by 20% in Add3KO rats. Neither were altered in WT rats. Proteinuria doubled in WT rats versus a sixfold increase in Add3KO rats. The degree of renal injury was greater in Add3KO than WT rats after 3 wk of hypertension. RBF, glomerular filtration rate, and glomerular capillary pressure were lower by 20%, 28%, and 19% in Add3KO rats than in WT rats, which was associated with glomerular matrix expansion and loss of capillary filtration area. The results indicated that impaired RBF autoregulation and eutrophic remodeling of preglomerular arterioles increase the transmission of pressure to glomeruli, which induces podocyte loss and accelerates the progression of CKD in hypertensive Add3KO rats.


Assuntos
Pressão Sanguínea , Taxa de Filtração Glomerular , Hipertensão/complicações , Glomérulos Renais/irrigação sanguínea , Proteinúria/etiologia , Circulação Renal , Insuficiência Renal Crônica/etiologia , Animais , Arteríolas/metabolismo , Arteríolas/fisiopatologia , Proteínas de Ligação a Calmodulina/genética , Proteínas de Ligação a Calmodulina/metabolismo , Acetato de Desoxicorticosterona , Modelos Animais de Doenças , Progressão da Doença , Homeostase , Hipertensão/genética , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Masculino , Desenvolvimento Muscular , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiopatologia , Proteinúria/genética , Proteinúria/metabolismo , Proteinúria/fisiopatologia , Ratos Transgênicos , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/fisiopatologia , Cloreto de Sódio na Dieta , Remodelação Vascular
13.
Hum Cell ; 33(4): 1036-1045, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32779153

RESUMO

The obstructive sleep apnea syndrome (OSAS) is a common sleep-related breathing disorder and an important cause of refractory hypertension. MicroRNAs (miRNAs) are involved in the development of hypertension, but their role in OSAS with hypertension (OSAS-hypertension) has been little studied. Evidence indicates that miR-126a-3p expression is lower in patients with OSAS-hypertension compared with the patients with OSAS alone. However, its role in the pathogenesis of OSAS-hypertension remains unclear. Therefore, this study aims to investigate the role of miR-126a-3p in OSAS-hypertension and to determine whether HIF-1α is involved in this process. Sprague Dawley rats were exposed to chronic intermittent hypoxia (CIH) for 8 weeks to induce OSAS-hypertension. Rat aortic smooth muscle cells (A7r5) were cultured under hypoxia as an in vitro model. Our results showed that rats exposed to 8 week CIH exhibited decreased miR-126a-3p and increased HIF-1α expression. Furthermore, administration of recombinant adeno-associated virus expressing miR-126a-3p (rAAV-miR-126a) counteracted the CIH-induced systolic blood pressure upregulation, oxidase stress, inflammation, and heart and abdominal aorta vascular remodeling. Moreover, the mechanism was associated with its targeted suppression of HIF-1α. These findings suggest that miR-126a-3p might be a novel potential therapeutic target for the treatment of OSAS-hypertension.


Assuntos
Expressão Gênica , Hipertensão/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Apneia Obstrutiva do Sono/genética , Animais , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/genética , Células Cultivadas , Hipertensão/etiologia , Hipertensão/terapia , Hipóxia/complicações , Hipóxia/fisiopatologia , Masculino , MicroRNAs/administração & dosagem , MicroRNAs/farmacologia , Terapia de Alvo Molecular , Ratos Sprague-Dawley , Apneia Obstrutiva do Sono/etiologia , Apneia Obstrutiva do Sono/terapia , Remodelação Vascular/efeitos dos fármacos , Remodelação Vascular/genética
14.
PLoS Comput Biol ; 16(8): e1007874, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32822340

RESUMO

Shear stress induces directed endothelial cell (EC) migration in blood vessels leading to vessel diameter increase and induction of vascular maturation. Other factors, such as EC elongation and interaction between ECs and non-vascular areas are also important. Computational models have previously been used to study collective cell migration. These models can be used to predict EC migration and its effect on vascular remodelling during embryogenesis. We combined live time-lapse imaging of the remodelling vasculature of the quail embryo yolk sac with flow quantification using a combination of micro-Particle Image Velocimetry and computational fluid dynamics. We then used the flow and remodelling data to inform a model of EC migration during remodelling. To obtain the relation between shear stress and velocity in vitro for EC cells, we developed a flow chamber to assess how confluent sheets of ECs migrate in response to shear stress. Using these data as an input, we developed a multiphase, self-propelled particles (SPP) model where individual agents are driven to migrate based on the level of shear stress while maintaining appropriate spatial relationship to nearby agents. These agents elongate, interact with each other, and with avascular agents at each time-step of the model. We compared predicted vascular shape to real vascular shape after 4 hours from our time-lapse movies and performed sensitivity analysis on the various model parameters. Our model shows that shear stress has the largest effect on the remodelling process. Importantly, however, elongation played an especially important part in remodelling. This model provides a powerful tool to study the input of different biological processes on remodelling.


Assuntos
Hidrodinâmica , Remodelação Vascular , Animais , Circulação Sanguínea , Movimento Celular/fisiologia , Forma Celular , Biologia Computacional , Células Endoteliais/fisiologia , Codorniz/anatomia & histologia , Codorniz/embriologia , Estresse Mecânico
15.
Nat Commun ; 11(1): 4311, 2020 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-32855420

RESUMO

Pulmonary disease increases the risk of developing abdominal aortic aneurysms (AAA). However, the mechanism underlying the pathological dialogue between the lungs and aorta is undefined. Here, we find that inflicting acute lung injury (ALI) to mice doubles their incidence of AAA and accelerates macrophage-driven proteolytic damage of the aortic wall. ALI-induced HMGB1 leaks and is captured by arterial macrophages thereby altering their mitochondrial metabolism through RIPK3. RIPK3 promotes mitochondrial fission leading to elevated oxidative stress via DRP1. This triggers MMP12 to lyse arterial matrix, thereby stimulating AAA. Administration of recombinant HMGB1 to WT, but not Ripk3-/- mice, recapitulates ALI-induced proteolytic collapse of arterial architecture. Deletion of RIPK3 in myeloid cells, DRP1 or MMP12 suppression in ALI-inflicted mice repress arterial stress and brake MMP12 release by transmural macrophages thereby maintaining a strengthened arterial framework refractory to AAA. Our results establish an inter-organ circuitry that alerts arterial macrophages to regulate vascular remodeling.


Assuntos
Lesão Pulmonar Aguda/complicações , Aneurisma da Aorta Abdominal/patologia , Proteína HMGB1/metabolismo , Macrófagos/metabolismo , Remodelação Vascular , Lesão Pulmonar Aguda/patologia , Animais , Aorta Abdominal/citologia , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/etiologia , Aneurisma da Aorta Abdominal/prevenção & controle , Células Cultivadas , Modelos Animais de Doenças , Dinaminas/antagonistas & inibidores , Dinaminas/metabolismo , Humanos , Macrófagos/citologia , Metaloproteinase 12 da Matriz/genética , Metaloproteinase 12 da Matriz/metabolismo , Camundongos , Camundongos Knockout , Dinâmica Mitocondrial/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fosforilação , Cultura Primária de Células , Proteólise/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/patologia , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Estudos Retrospectivos , Regulação para Cima
16.
Life Sci ; 258: 118156, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32735886

RESUMO

AIMS: Flavin adenine dinucleotide (FAD), participates in fatty acid ß oxidation as a cofactor, which has been confirmed to enhance SCAD activity and expression. However, the role of FAD on hypertensive vascular remodeling is unclear. In this study, we investigated the underlying mechanisms of FAD on vascular remodeling and endothelial homeostasis. MAIN METHODS: Morphological examination of vascular remodeling were analyzed with hematoxylin and eosin (HE) staining, Verhoeff's Van Gieson (EVG) staing, Dihydroethidium (DHE) staining and Sirius red staining. HUVECs apoptotic rate was detected by flow cytometry and HUVECs reactive oxygen species (ROS) was detected by DHE-probe. Enzymatic reactions were used to detect SCAD enzyme activity. The protein level was detected by Western Blots, the mRNA level was detected by quantitative real-time PCR. KEY FINDINGS: In vivo experiments, FAD significantly decreased blood pressure and ameliorated vascular remodeling by increasing SCAD expression, Nitric Oxide (NO) production and reducing ROS production. In vitro experiments, FAD protected against the tBHP induced injury in HUVEC, by increasing the activity of SCAD, increasing the elimination of free fatty acid (FFA), scavenging ROS, reducing apoptotic rate, thereby improving endothelial cell function. SIGNIFICANCE: FAD has a new possibility for preventing and treating hypertensive vascular remodeling.


Assuntos
Acil-CoA Desidrogenases/metabolismo , Ativadores de Enzimas/uso terapêutico , Flavina-Adenina Dinucleotídeo/uso terapêutico , Hipertensão/tratamento farmacológico , Remodelação Vascular/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Ativadores de Enzimas/farmacologia , Flavina-Adenina Dinucleotídeo/farmacologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Masculino , Ratos Endogâmicos SHR , Ratos Wistar
18.
Eur J Vasc Endovasc Surg ; 60(3): 386-393, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32741679

RESUMO

OBJECTIVE: The current treatment for acute retrograde type A intramural haematoma (IMH) remains challenging. Aortic remodelling in both the ascending aorta (AA) and descending thoracic aorta (DTA) was evaluated and the 30 day and mid term outcomes were determined in patients who underwent thoracic endovascular aneurysm repair (TEVAR) for retrograde type A IMH with a primary intimal tear or ulcer like projection in the DTA METHODS: This was a retrospective, multicentre observational study. Clinical data, including post-operative mortality and adverse event, aorta related re-intervention, aortic remodelling, and the survival rate of 18 non-consecutive patients with acute retrograde type A IMH undergoing TEVAR between June 2006 and March 2018 were reviewed. RESULTS: The median age at repair was 58.1 years (range 38-86) and 14 (78%) were men. Eight patients (44%) presented with haemopericardium, and 10 (56%) underwent TEVAR within 24 h. The mean IMH thickness and AA diameter were 10.4 ± 3.6 and 45.7 ± 4.6 mm, respectively. Among all patients with acute retrograde type A IMH, 11 patients presented with classical type B aortic dissection and seven with type B IMH. All procedures were technically successful. The median follow up was 28.7 months (range 7-78). No 30 day mortality was observed. Three patients developed post-procedure adverse events. Of these, two patients had neurological events, with one each having cerebrovascular and spinal cord infarction individually, and the third patient required long term haemodialysis with ventilator support. The overall survival rate was 100%. The maximum diameter of the AA and the IMH in the AA significantly decreased after TEVAR. Aortic remodelling was also observed in the DTA along the length of TEVAR coverage. CONCLUSION: In selected patients with acute retrograde type A IMH, TEVAR offered a treatment alternative to open surgical grafting and medical follow up.


Assuntos
Aorta Torácica/cirurgia , Doenças da Aorta/cirurgia , Implante de Prótese Vascular , Procedimentos Endovasculares , Hematoma/cirurgia , Remodelação Vascular , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Aorta Torácica/diagnóstico por imagem , Aorta Torácica/fisiopatologia , Doenças da Aorta/diagnóstico por imagem , Doenças da Aorta/fisiopatologia , Prótese Vascular , Implante de Prótese Vascular/efeitos adversos , Implante de Prótese Vascular/instrumentação , Procedimentos Endovasculares/efeitos adversos , Procedimentos Endovasculares/instrumentação , Feminino , Hematoma/diagnóstico por imagem , Hematoma/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Fatores de Risco , Stents , Taiwan , Fatores de Tempo , Resultado do Tratamento
19.
Proc Natl Acad Sci U S A ; 117(29): 17369-17380, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32641503

RESUMO

Voltage-gated L-type Ca2+ channel (Cav1.2) blockers (LCCBs) are major drugs for treating hypertension, the preeminent risk factor for heart failure. Vascular smooth muscle cell (VSMC) remodeling is a pathological hallmark of chronic hypertension. VSMC remodeling is characterized by molecular rewiring of the cellular Ca2+ signaling machinery, including down-regulation of Cav1.2 channels and up-regulation of the endoplasmic reticulum (ER) stromal-interacting molecule (STIM) Ca2+ sensor proteins and the plasma membrane ORAI Ca2+ channels. STIM/ORAI proteins mediate store-operated Ca2+ entry (SOCE) and drive fibro-proliferative gene programs during cardiovascular remodeling. SOCE is activated by agonists that induce depletion of ER Ca2+, causing STIM to activate ORAI. Here, we show that the three major classes of LCCBs activate STIM/ORAI-mediated Ca2+ entry in VSMCs. LCCBs act on the STIM N terminus to cause STIM relocalization to junctions and subsequent ORAI activation in a Cav1.2-independent and store depletion-independent manner. LCCB-induced promotion of VSMC remodeling requires STIM1, which is up-regulated in VSMCs from hypertensive rats. Epidemiology showed that LCCBs are more associated with heart failure than other antihypertensive drugs in patients. Our findings unravel a mechanism of LCCBs action on Ca2+ signaling and demonstrate that LCCBs promote vascular remodeling through STIM-mediated activation of ORAI. Our data indicate caution against the use of LCCBs in elderly patients or patients with advanced hypertension and/or onset of cardiovascular remodeling, where levels of STIM and ORAI are elevated.


Assuntos
Canais de Cálcio Tipo L/metabolismo , Hipertensão/metabolismo , Molécula 1 de Interação Estromal/metabolismo , Molécula 2 de Interação Estromal/metabolismo , Moléculas de Interação Estromal/metabolismo , Remodelação Vascular/fisiologia , Animais , Anti-Hipertensivos/farmacologia , Cálcio/metabolismo , Canais de Cálcio Tipo L/efeitos dos fármacos , Membrana Celular/metabolismo , Movimento Celular , Proliferação de Células , Modelos Animais de Doenças , Retículo Endoplasmático/metabolismo , Técnicas de Inativação de Genes , Células HEK293 , Insuficiência Cardíaca , Humanos , Proteínas de Membrana/genética , Miócitos de Músculo Liso , Proteínas de Neoplasias , Proteína ORAI1/genética , Ratos , Molécula 1 de Interação Estromal/genética , Molécula 2 de Interação Estromal/genética
20.
Int J Cardiovasc Imaging ; 36(11): 2105-2106, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32686029

RESUMO

A patient with Takayasu arteritis who underwent CABG using a saphenous vein graft (SVG) experienced ventricular fibrillation due to total SVG occlusion. A drug-eluting stent was implanted; however, follow-up CAG demonstrated an advanced expansion of peri-stent contrast staining. Coronary computed tomography angiography revealed contrast media extending around the SVG. An intravascular ultrasound indicated a worsening stent malapposition and a significant positive remodeling.


Assuntos
Falso Aneurisma/cirurgia , Aneurisma Coronário/cirurgia , Ponte de Artéria Coronária/efeitos adversos , Stents Farmacológicos , Oclusão de Enxerto Vascular/terapia , Imagem Multimodal , Intervenção Coronária Percutânea/instrumentação , Veia Safena/transplante , Falso Aneurisma/diagnóstico por imagem , Falso Aneurisma/etiologia , Angiografia por Tomografia Computadorizada , Aneurisma Coronário/diagnóstico por imagem , Aneurisma Coronário/etiologia , Angiografia Coronária , Feminino , Oclusão de Enxerto Vascular/diagnóstico por imagem , Oclusão de Enxerto Vascular/etiologia , Humanos , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/efeitos adversos , Valor Preditivo dos Testes , Veia Safena/diagnóstico por imagem , Arterite de Takayasu/complicações , Arterite de Takayasu/diagnóstico , Resultado do Tratamento , Ultrassonografia de Intervenção , Remodelação Vascular
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA