RESUMO
Vasculogenic mimicry (VM) is an endothelium-independent tumor microcirculation that provides adequate blood supply for tumor growth. The presence of VM greatly hinders the treatment of glioblastoma (GBM) with anti-angiogenic drugs. Therefore, targeting VM formation may be a feasible therapeutic strategy for GBM. The research aimed to evaluate the roles of BUD13, CDK12, MBNL1 in regulating VM formation of GBM. BUD13 and CDK12 were upregulated and MBNL1 was downregulated in GBM tissues and cells. Knockdown of BUD13, CDK12, or overexpression of MBNL1 inhibited GBM VM formation. METTL3 enhanced the stability of BUD13 mRNA and upregulated its expression through m6A methylation. BUD13 enhanced the stability of CDK12 mRNA and upregulated its expression. CDK12 phosphorylated MBNL1, thereby regulating VM formation of GBM. The simultaneous knockdown of BUD13, CDK12, and overexpression of MBNL1 reduced the volume of subcutaneously transplanted tumors in nude mice and prolonged the survival period. Thus, the BUD13/CDK12/MBNL1 axis plays a crucial role in regulating VM formation of GBM and provides a potential target for GBM therapy.
Assuntos
Quinases Ciclina-Dependentes , Proteínas de Ligação a DNA , Glioblastoma , Metiltransferases , Proteínas de Ligação a RNA , Animais , Camundongos , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Glioblastoma/irrigação sanguínea , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Metilação , Camundongos Nus , Fosforilação , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Quinases Ciclina-Dependentes/genética , Quinases Ciclina-Dependentes/metabolismo , Metiltransferases/genética , Metiltransferases/metabolismo , Microcirculação/genética , Microcirculação/fisiologia , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismoRESUMO
BACKGROUND: Type 2 Diabetes Mellitus (T2DM) is a chronic metabolic condition with various genetics and environmental influences that affects the capacity of the body to produce or use insulin resulting in hyperglycemia, which may lead to variable complications. It is one of the world's rising health problems. There is emerging evidence that some genetic polymorphisms can impact the risk of evolving T2DM. We try to determine the relationship of (rs7903146) variant of the Transcription factor 7-like 2 (TCF7L2) gene with T2DM and its microvascular complications. METHODS AND RESULTS: This case-control study included 180 subjects: 60 diabetic patients without complications, 60 diabetic patients with microvascular complications and 60 matched healthy controls. Genotypes of rs7903146 (C/T) SNP in the TCF7L2 gene were evaluated by real-time polymerase chain reaction via TaqMan allelic discrimination. Logistic regression was used to detect the most independent factor for development of diabetes and diabetic microvascular complications. Variant homozygous TT and heterozygous CT genotypes were significantly increased in diabetic without complications and diabetic with complications groups than controls (p = 0.003, 0.001) respectively. The T allele was more represented in both patient groups than controls with no significant difference between patient groups. TT genotype as well as T allele was significantly associated with increased T2DM risk. CONCLUSION: The T allele of rs7903146 polymorphism of TCF7L2 confers susceptibility to development of T2DM. However, no significant association was found for diabetic complications.
Assuntos
Diabetes Mellitus Tipo 2/genética , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Adulto , Alelos , Estudos de Casos e Controles , Angiopatias Diabéticas/complicações , Angiopatias Diabéticas/genética , Egito/epidemiologia , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Microcirculação/genética , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fatores de RiscoRESUMO
Neuromodulation of immune function by stimulating the autonomic connections to the spleen has been demonstrated in rodent models. Consequently, neuroimmune modulation has been proposed as a new therapeutic strategy for the treatment of inflammatory conditions. However, demonstration of the translation of these immunomodulatory mechanisms in anatomically and physiologically relevant models is still lacking. Additionally, translational models are required to identify stimulation parameters that can be transferred to clinical applications of bioelectronic medicines. Here, we performed neuroanatomical and functional comparison of the mouse, rat, pig, and human splenic nerve using in vivo and ex vivo preparations. The pig was identified as a more suitable model of the human splenic innervation. Using functional electrophysiology, we developed a clinically relevant marker of splenic nerve engagement through stimulation-dependent reversible reduction in local blood flow. Translation of immunomodulatory mechanisms were then assessed using pig splenocytes and two models of acute inflammation in anesthetized pigs. The pig splenic nerve was shown to locally release noradrenaline upon stimulation, which was able to modulate cytokine production by pig splenocytes. Splenic nerve stimulation was found to promote cardiovascular protection as well as cytokine modulation in a high- and a low-dose lipopolysaccharide model, respectively. Importantly, splenic nerve-induced cytokine modulation was reproduced by stimulating the efferent trunk of the cervical vagus nerve. This work demonstrates that immune responses can be modulated by stimulation of spleen-targeted autonomic nerves in translational species and identifies splenic nerve stimulation parameters and biomarkers that are directly applicable to humans due to anatomical and electrophysiological similarities.
Assuntos
Sistema Imunitário/inervação , Imunomodulação/efeitos dos fármacos , Baço/imunologia , Sistema Nervoso Simpático/imunologia , Nervo Vago/imunologia , Animais , Feminino , Expressão Gênica , Humanos , Sistema Imunitário/efeitos dos fármacos , Inflamação , Interleucina-6/genética , Interleucina-6/imunologia , Lipopolissacarídeos/farmacologia , Camundongos , Microcirculação/efeitos dos fármacos , Microcirculação/genética , Microcirculação/imunologia , Norepinefrina/farmacologia , Ratos , Especificidade da Espécie , Baço/efeitos dos fármacos , Baço/inervação , Baço/patologia , Suínos , Sistema Nervoso Simpático/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Nervo Vago/efeitos dos fármacos , Estimulação do Nervo Vago/métodosAssuntos
Anemia Falciforme/genética , Deleção de Genes , Microcirculação/genética , alfa-Globinas/deficiência , Talassemia alfa/genética , Adolescente , Adulto , Anemia Falciforme/sangue , Anemia Falciforme/complicações , Anemia Falciforme/fisiopatologia , Velocidade do Fluxo Sanguíneo , Pressão Sanguínea , Índice de Massa Corporal , Criança , Índices de Eritrócitos , Feminino , Dedos/irrigação sanguínea , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Óxido Nítrico/fisiologia , Vasodilatação , Adulto Jovem , alfa-Globinas/genética , Talassemia alfa/sangue , Talassemia alfa/complicações , Talassemia alfa/fisiopatologiaRESUMO
Previous reports reveal that +9/-9 polymorphism of the bradykinin B2 receptor (BDKRB2) is suggestive of cardiometabolic diseases. The aim of this study was to examine the impact of BDKRB2 + 9/-9 polymorphism genotypes on the blood pressure parameters and microvascular function in prepubescent children. We screened for BDKRB2 + 9/-9 polymorphism in the DNA of 145 children (86 boys and 59 girls), and its association with body composition, blood pressure levels, biochemical parameters, and endothelial function was determined. No significant association of the BDKRB2 genotypes with gender (P=0.377), race (P=0.949) or family history of cardiovascular disease (CVD) (P=0.858) was observed. Moreover, we did not identify any interaction between BDKRB2 genotypes with a phenotype of obesity (P=0.144). Children carrying the +9/+9 genotype exhibited a significant linear trend with higher levels of systolic blood pressure and pulse pressure (P<0.001). Moreover, the presence of +9 allele resulted in a decrease of reactive hyperemia index, showing a decreasing linear trend from -9/-9 to +9/+9, wherein this parameter of endothelial function was the lowest in the +9/+9 children, intermediate in the +9/-9 children, and the highest in the -9/-9 children (P<0.001). There was a significant inverse correlation between reactive hyperemia index and systolic blood pressure (r= - 0.348, P< 0.001) and pulse pressure (r= - 0.399, P< 0.001). Our findings indicate that the +9/+9 BDKRB2 genotype was associated with high blood pressure and microvascular dysfunction in prepubescent Brazilian children.
Assuntos
Pressão Sanguínea/genética , Síndrome Metabólica/genética , Microcirculação/genética , Polimorfismo Genético , Receptor B2 da Bradicinina/genética , População Negra/genética , Brasil/epidemiologia , Criança , Feminino , Genótipo , Humanos , Hiperemia/genética , Hiperemia/fisiopatologia , Hipertensão/genética , Hipertensão/fisiopatologia , Masculino , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/fisiopatologia , Grupos Raciais/genética , População Branca/genéticaRESUMO
BACKGROUND: Microvascular obstruction (MVO) can result in coronary microcirculation embolism and myocardial microinfarction. Myocardial injury induced by MVO is characterized by continuous ischemia and hypoxia of cardiomyocytes. Autophagy and apoptosis are closely associated with various cardiovascular diseases. Based on our previous study, we observed a decrease in miR-30e-3p expression and an increase in Egr-1 expression in a rat coronary microembolization model. However, the specific function of miR-30e-3p in regulating autophagy and apoptosis in an ischemia/hypoxia (IH) environment remains to be deciphered. We exposed cardiomyocytes to an IH environment and then determined whether miR-30e-3p was involved in promoting cardiomyocyte autophagy and inhibiting apoptosis by regulating Egr-1. METHODS: Cardiomyocytes were isolated from rats for our in vitro study. miR-30e-3p was either overexpressed or inhibited by transfection with lentiviral vectors into cardiomyocytes. 3-Methyladenine (3-MA) was used to inhibit autophagy. RT-qPCR and western blotting were used to determine the expression levels of miR-30e-3p, Egr-1, and proteins related to the autophagy and apoptosis process. Autophagic vacuoles and autophagic flux were evaluated using transmission electron microscopy (TEM) and confocal microscopy, respectively. Cardiomyocyte viability was evaluated using the MTS assay. Cell injury was assessed by lactate dehydrogenase (LDH) leakage, and apoptosis was determined by flow cytometry. RESULTS: Both miR-30e-3p expression and autophagy were significantly inhibited, and apoptosis was increased in cardiomyocytes after 9 hours of IH exposure. Overexpression of miR-30e-3p increased autophagy and inhibited apoptosis, as well as suppressed Egr-1 expression and decreased cell injury. In addition, inhibition of miR-30e-3p reduced autophagy and increased apoptosis and cell injury. CONCLUSIONS: miR-30e-3p may be involved in promoting cardiomyocyte autophagy and inhibiting apoptosis by indirectly regulating Egr-1 expression in an IH environment.
Assuntos
Proteína 1 de Resposta de Crescimento Precoce/metabolismo , MicroRNAs/genética , Isquemia Miocárdica/patologia , Miócitos Cardíacos/patologia , Animais , Animais Recém-Nascidos , Apoptose/fisiologia , Autofagossomos/genética , Autofagossomos/patologia , Autofagia/genética , Autofagia/fisiologia , Hipóxia Celular/genética , Células Cultivadas , Proteína 1 de Resposta de Crescimento Precoce/genética , Regulação da Expressão Gênica , Microcirculação/genética , Microscopia Confocal , Isquemia Miocárdica/genética , Miócitos Cardíacos/fisiologia , Ratos Sprague-DawleyRESUMO
Microcirculation maintenance is associated with microRNAs. Nevertheless, the role of microRNAs induced by training in preventing dexamethasone (DEX)-induced microvascular rarefaction remains unknown. The study aim was to investigate if training-induced microRNAs are able to improve microcirculation proteins and prevent DEX-induced microvascular rarefaction. Rats underwent training for 8 weeks and then were treated with DEX (50 µg/kg per day, s.c.) for 14 days. Arterial pressure was measured and tibialis anterior (TA) muscle was collected for analyses. DEX induced hypertension concomitantly with capillary density loss (CD, -23.9%) and decrease of VEGF (-43.0%), p-AKT/AKT (-39.6%) and Bcl-2 (-23.0%) and an increase in caspase-3-cleaved protein level (+34.0%) in TA muscle. Training upregulated microRNA-126 expression (+13.1%), prevented VEGF (+61.4%), p-AKT/AKT (+37.7%), Bcl-2 (+7.7%) decrease and caspase-3-cleaved (-23.1%) increase associated with CD (+54.7%) reduction and hypertension prevention. MiRNA-126 upregulation, induced by training, plays a role in controlling microcirculation, which may be a potential target against DEX-induced microvascular rarefaction.
Assuntos
Dexametasona/farmacologia , MicroRNAs/genética , Microcirculação/genética , Condicionamento Físico Animal , Regulação para Cima/genética , Glândulas Suprarrenais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Capilares/efeitos dos fármacos , Capilares/fisiologia , Hemodinâmica/efeitos dos fármacos , Masculino , MicroRNAs/metabolismo , Microcirculação/efeitos dos fármacos , Músculo Esquelético/irrigação sanguínea , Tamanho do Órgão/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Wistar , Regulação para Cima/efeitos dos fármacosRESUMO
Chest pain with non-obstructive coronary artery disease (NOCAD) occurs more frequently in women than in men and is mainly related to coronary microvascular disease (CMD). The majority of CMD patients are postmenopausal women, suggesting a role for lack of estrogens in the development and progression of CMD. Patients are often discharged without a clear treatment plan due to the limited understanding of etiology and diagnostic parameters of CMD and have significantly higher rates of future cardiovascular events. Thus, there is a need for a better understanding of the underlying biology, and CMD-specific diagnostic tests and therapies. In this article, we reviewed recent studies on CMD, estrogen action in coronary microvasculature, and diagnosis and treatment options for CMD in postmenopausal women.
Assuntos
Doença da Artéria Coronariana , Receptores de Estrogênio/fisiologia , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/fisiopatologia , Estrogênios/deficiência , Estrogênios/farmacologia , Feminino , Humanos , Masculino , Microcirculação/efeitos dos fármacos , Microcirculação/genética , Microcirculação/fisiologia , Pós-Menopausa/fisiologia , Caracteres Sexuais , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genéticaRESUMO
Cerebral small-vessel disease (cSVD) is a common cause of stroke, functional decline, vascular cognitive impairment, and dementia. Pathological processes in the brain's microcirculation are tightly interwoven with pathology in the brain parenchyma, and this interaction has been conceptualized as the neurovascular unit (NVU). Despite intensive research efforts to decipher the NVU's structure and function to date, molecular mechanisms underlying cSVD remain poorly understood, which hampers the development of cSVD-specific therapies. Important steps forward in understanding the disease mechanisms underlying cSVD have been made using genetic approaches in studies of both monogenic and sporadic SVD. We provide an overview of the NVU's structure and function, the implications for cSVD, and the underlying molecular mechanisms of dysfunction that have emerged from recent genetic studies of both monogenic and sporadic diseases of the small cerebral vasculature.
Assuntos
Encéfalo/irrigação sanguínea , Doenças de Pequenos Vasos Cerebrais/genética , Circulação Cerebrovascular/genética , Acidente Vascular Cerebral/genética , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/patologia , Doenças de Pequenos Vasos Cerebrais/tratamento farmacológico , Doenças de Pequenos Vasos Cerebrais/patologia , Disfunção Cognitiva/genética , Disfunção Cognitiva/patologia , Humanos , Microcirculação/genética , Neuroimagem , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/patologiaRESUMO
Background We previously found that the structural defects of the coronary collateral microcirculation reserve (CCMR) prevent these preformed collateral vessels from continuously delivering the native collateral blood and supporting the ischemic myocardium in rats. Here, we tested whether these native collaterals can be remodeled by artificially increasing pigment epithelium-derived factor (PEDF) expression and demonstrated the mechanism for this stimulation. Methods and Results We performed intramyocardial gene delivery (PEDF-lentivirus, 2×107 TU) along the left anterior descending coronary artery to artificially increase the expression of PEDF in the tissue of the region for 2 weeks. By blocking the left anterior descending coronary artery, we examined the effects of PEDF on native collateral blood flow and CCMR. The results of positron emission tomography perfusion imaging showed that PEDF increased the native collateral blood flow and significantly inhibited its decline during acute myocardial infarction. In addition, the number of CCMR vessels decreased and the size increased. Similar results were obtained from in vitro experiments. We tested whether PEDF induces CCMR remodeling in a fluid shear stress-like manner by detecting proteins and signaling pathways that are closely related to fluid shear stress. The nitric oxide pathway and the Notch-1 pathway participated in the process of CCMR remodeling induced by PEDF. Conclusions PEDF treatment activates the nitric oxide pathway, and the Notch-1 pathway enabled CCMR remodeling. Increasing the native collateral blood flow can promote the ventricular remodeling process and improve prognosis after acute myocardial infarction.
Assuntos
Aterosclerose/genética , Circulação Colateral/genética , Vasos Coronários/fisiopatologia , Proteínas do Olho/genética , Infarto do Miocárdio/fisiopatologia , Fatores de Crescimento Neural/genética , Serpinas/genética , Remodelação Vascular/genética , Remodelação Ventricular/genética , Animais , Circulação Colateral/fisiologia , Células Endoteliais/efeitos dos fármacos , Proteínas do Olho/farmacologia , Técnicas de Transferência de Genes , Vetores Genéticos , Humanos , Lentivirus , Microcirculação/genética , Microcirculação/fisiologia , Isquemia Miocárdica/fisiopatologia , Reperfusão Miocárdica , Miocárdio , Fatores de Crescimento Neural/farmacologia , Óxido Nítrico/metabolismo , Tomografia por Emissão de Pósitrons , Ratos , Receptor Notch1/metabolismo , Serpinas/farmacologia , Estresse MecânicoRESUMO
Septic patients often die in a context of multiple organ dysfunction syndrome (MODS), despite the macro-hemodynamic parameters being normalized and after the onset of antibiotic therapy. Microcirculation injury during sepsis affects capillary permeability and leukocyte-endothelium interactions and is thought to be instrumental in organ injury. Several studies have demonstrated a beneficial effect of mesenchymal stromal cells (MSCs) injection on survival and organ dysfunctions in sepsis models. In vivo activity of MSCs also appears to be very much dependent on the information provided before injection. Indeed preconditioning by interferon γ (IFNγ; MSC-IFNγ) increases immunosuppressive capacity of MSCs in vitro and in vivo. Therefore, the objective was to evaluate the effect of MSC naive or IFNγ preconditioned on leukocyte-endothelium interactions in a polymicrobial sepsis model by intraperitoneal feces injection. Six hours (H6) after this induction, we used intravital microscopy in mice cremaster muscle venules to study the flow behavior of leukocytes. Plasmas were harvested to evaluate inflammation level and endothelial activation. We showed that MSC-IFNγ have a beneficial effect on microcirculation, by increasing the flow of white blood cells (WBCs) and the percentage of venules containing flowing WBCs, by significantly reducing the adhesion of WBCs and by increasing the average red blood cell velocity (VRBC). In conclusion, our results suggest that intravenous injection of preconditioned MSC-IFNγ improves microvascular hemodynamics in early phases of sepsis.
Assuntos
Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Microvasos/citologia , Sepse/terapia , Animais , Adesão Celular/genética , Adesão Celular/fisiologia , Meios de Cultivo Condicionados/farmacologia , Modelos Animais de Doenças , Endotélio/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Humanos , Interferon gama/genética , Leucócitos/efeitos dos fármacos , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos , Microcirculação/genética , Microcirculação/fisiologia , Microvasos/metabolismo , Sepse/patologiaRESUMO
Obesity-associated chronic inflammation in adipose tissue is partly attributed to hypoxia with insufficient microcirculation. Previous studies have shown that exenatide, a glucagon-like peptide 1 (GLP-1) receptor agonist, plays an anti-inflammatory role. Here, we investigate its effects on inflammation, hypoxia and microcirculation in white adipose tissue of diet-induced obese (DIO) mice. DIO mice were injected intraperitoneally with exenatide or normal saline for 4 weeks, while mice on chow diet were used as normal controls. The mRNA and protein levels of pro-inflammatory cytokines, hypoxia-induced genes and angiogenic factors were detected. Capillary density was measured by laser confocal microscopy and immunochemistry staining. After 4-week exenatide administration, the dramatically elevated pro-inflammatory cytokines in serum and adipose tissue and macrophage infiltration in adipose tissue of DIO mice were significantly reduced. Exenatide also ameliorated expressions of hypoxia-related genes in obese fat tissue. Protein levels of endothelial markers and pro-angiogenic factors including vascular endothelial growth factor and its receptor 2 were augmented in accordance with increased capillary density by exenatide in DIO mice. Our results indicate that inflammation and hypoxia in adipose tissue can be mitigated by GLP-1 receptor agonist potentially via improved angiogenesis and microcirculation in obesity.
Assuntos
Tecido Adiposo Branco/efeitos dos fármacos , Exenatida/farmacologia , Inflamação/prevenção & controle , Microcirculação/efeitos dos fármacos , Obesidade/prevenção & controle , Tecido Adiposo Branco/irrigação sanguínea , Tecido Adiposo Branco/metabolismo , Animais , Fármacos Antiobesidade/administração & dosagem , Fármacos Antiobesidade/farmacologia , Citocinas/sangue , Citocinas/genética , Citocinas/metabolismo , Dieta Hiperlipídica/efeitos adversos , Exenatida/administração & dosagem , Expressão Gênica/efeitos dos fármacos , Hipóxia/genética , Hipóxia/metabolismo , Inflamação/genética , Inflamação/metabolismo , Injeções Intraperitoneais , Masculino , Camundongos Endogâmicos C57BL , Microcirculação/genética , Microcirculação/fisiologia , Obesidade/etiologia , Obesidade/genéticaRESUMO
Vascular endothelial cells line the inner surface of the entire cardiovascular system as a single layer and are involved in an impressive array of functions, ranging from the regulation of vascular tone in resistance arteries and arterioles, modulation of microvascular barrier function in capillaries and postcapillary venules, and control of proinflammatory and prothrombotic processes, which occur in all segments of the vascular tree but can be especially prominent in postcapillary venules. When tissues are subjected to ischemia/reperfusion (I/R), the endothelium of resistance arteries and arterioles, capillaries, and postcapillary venules become dysfunctional, resulting in impaired endothelium-dependent vasodilator and enhanced endothelium-dependent vasoconstrictor responses along with increased vulnerability to thrombus formation, enhanced fluid filtration and protein extravasation, and increased blood-to-interstitium trafficking of leukocytes in these functionally distinct segments of the microcirculation. The number of capillaries open to flow upon reperfusion also declines as a result of I/R, which impairs nutritive perfusion. All of these pathologic microvascular events involve the formation of reactive species (RS) derived from molecular oxygen and/or nitric oxide. In addition to these effects, I/R-induced RS activate NLRP3 inflammasomes, alter connexin/pannexin signaling, provoke mitochondrial fission, and cause release of microvesicles in endothelial cells, resulting in deranged function in arterioles, capillaries, and venules. It is now apparent that this microvascular dysfunction is an important determinant of the severity of injury sustained by parenchymal cells in ischemic tissues, as well as being predictive of clinical outcome after reperfusion therapy. On the other hand, RS production at signaling levels promotes ischemic angiogenesis, mediates flow-induced dilation in patients with coronary artery disease, and instigates the activation of cell survival programs by conditioning stimuli that render tissues resistant to the deleterious effects of prolonged I/R. These topics will be reviewed in this article.
Assuntos
Isquemia/metabolismo , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/metabolismo , Arteríolas/metabolismo , Arteríolas/patologia , Adesão Celular/genética , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Humanos , Isquemia/genética , Isquemia/patologia , Leucócitos/metabolismo , Microcirculação/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR , Óxido Nítrico/metabolismo , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/patologiaRESUMO
BACKGROUND: Microvascular obstruction (MVO) after primary percutaneous coronary intervention (pPCI) leads to higher incidence of both early and late complications. A number of single nucleotide polymorphisms in 9p21 chromosome have been shown to affect angiogenesis in response to ischaemia. In particular, Rs1333040 with its three genotypic vriants C/C, T/C and T/T might influence the occurrence of MVO after pPCI. METHODS: We enrolled ST-elevation myocardial infarction (STEMI) patients undergoing pPCI. The Rs1333040 polymorphism was evaluated by polymerase chain reaction-restriction fragment length polymorphism using restriction endonucleases (Bsml). Two expert operators unaware of the patients' identity performed the angiographic analysis; collaterals were assessed applying Rentrop's classification. Angiographic MVO was defined as a post-pPCI Thrombolysis In Myocardial Infarction (TIMI)<3 or TIMI 3 with myocardial blush grade 0 or 1, whereas electrocardiographic MVO was defined as ST segment resolution <70% one hour after pPCI. RESULTS: Among our 133 STEMI patients (mean age 63 ± 11 years, men 72%), 35 (26%) and 53 (40%) respectively experienced angiographic or electrocardiographic MVO. Angiographic and electrocardiographic MVO were different among the three variants (p= 0.03 and p=0.02 respectively). In particular, T/T genotype was associated with a higher incidence of both angiographic and electrocardiographic MVO compared with C/C genotype (p=0.04 and p=0.03 respectively). Moreover, Rentrop score <2 detection rate differed among the three genotypes (p=0.03). In particular T/T genotype was associated with a higher incidence of a Rentrop score <2 as compared with C/C genotype (p= 0.02). CONCLUSION: Rs1333040 polymorphism genetic variants portend different MVO incidence. In particular, T/T genotype is related to angiographic and electrocardiographic MVO and to worse collaterals towards the culprit artery.
Assuntos
Oclusão Coronária/complicações , Inibidor de Quinase Dependente de Ciclina p21/genética , Neovascularização Fisiológica/genética , Intervenção Coronária Percutânea/efeitos adversos , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Síndrome Coronariana Aguda/metabolismo , Idoso , Angioplastia/métodos , Cromossomos Humanos Par 9/genética , Angiografia Coronária/métodos , Oclusão Coronária/diagnóstico por imagem , Oclusão Coronária/epidemiologia , Oclusão Coronária/patologia , Vasos Coronários/patologia , Eletrocardiografia/métodos , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Incidência , Masculino , Microcirculação/genética , Microcirculação/fisiologia , Pessoa de Meia-Idade , Infarto do Miocárdio/terapia , Polimorfismo de Nucleotídeo Único/genética , Infarto do Miocárdio com Supradesnível do Segmento ST/genética , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia , Terapia Trombolítica/métodosRESUMO
BACKGROUND: The laser Doppler fluxmetry (LDF) is a non-invasive method to assess skin blood perfusion, measuring the flow of blood cells inside a tissue volume without harming the tissue. In the diagnosis of skin circulation disorders, the results of the LDF measurement are generally used in such a way that "normal" (or non-ill) or "pathological" values are achieved by comparison with a reference sample, for example of apparently healthy subjects. MATERIAL AND METHODS: In this study, the values of LDF for the diagnosis of microcirculatory disorders in patients with coronary artery disease (nâ=â20) or in patients with microcirculatory disorders, already diagnosed by capillary microscopy (nâ=â46), were examined. RESULTS: The mean values of LD amplitudes in the four frequency windows for patients with coronary artery disease were in the reference range. However, some of the patients showed reduced LD values: in eleven of the twenty patients, one or more mean LD amplitudes were below the reference range. Four of the eleven patients had pathologically decreased capillary erythrocyte velocities of veryâ=â0.09-0.21 [mm/s], while the other seven patients had normal blood circulation at rest.For all patients with a proven cutaneous microcirculatory disorder, the mean LD amplitude in at least one of the frequency windows FF2 to FF4 was pathologically reduced. CONCLUSION: The Laser-Doppler fluxmetry method used in the study allows the reliable diagnosis of cutaneous microcirculatory disorders.
Assuntos
Fluxometria por Laser-Doppler/métodos , Microcirculação/genética , Adulto , Doença da Artéria Coronariana , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Dyslipidemia is widely accepted as one of the major risk factors in cardiovascular disease mainly due to its contribution in the pathogenesis of atherosclerosis in medium-sized and large arteries. However, it has become increasingly accepted that high-cholesterol levels can also adversely affect the microvasculature prior to the development of overt atherosclerosis. Moreover, hypercholesterolemia has shown, in preclinical animal models, to exert detrimental effects beyond the vascular tree leading to larger infarcts and adverse cardiac remodeling post-myocardial infarction. At a functional level, hypercholesterolemia has shown to impair endotheliumdependent vasodilation because on defects on nitric oxide bioavailability. The pathogenic mechanisms underlying microvascular dysfunction involve an enhanced arginase activity, enhanced production of free radicals and the activation, recruitment and accumulation of leukocytes, primarily neutrophils, via their diffusion through postcapillary venules. In turn, recruited inflammatory cells and certain inflammatory mediators enhance platelet adhesion, overall inducing a proinflammatory and prothrombotic phenotype. Within the present review, we aim to discuss the existing evidence regarding the presence of dyslipidemia - particularly high low density lipoprotein-cholesterol levels - and the occurrence of microvascular dysfunction, the mechanism by which high cholesterol levels induce functional alterations in the microvascular bed and, finally comment on the impact of dislipidemia-induced microvascular dysfunction at the myocardial level.
Assuntos
Dislipidemias/genética , Microcirculação/genética , Animais , Dislipidemias/metabolismo , HumanosRESUMO
BACKGROUND: Intermittent ischemia in remote tissues can be applied before ischemic injury, during ischemic injury or at the beginning of reperfusion of an index organ ischemia. The aim of this study was to investigate the effect of Remote Ischemic Conditioning (RIC) of the leg on changes in ischemia-induced the microvascular functions of the arm. MATERIAL AND METHODS: Ischemic microvascular injury was induced by arm ischemia (20âmin) and reperfusion in healthy, nonsmoker, male volunteers (ischemia group-ISC, n: 9). In another group of volunteers, to investigate the effects of remote organ ischemic conditioning 5 cycles of reperfusion followed by leg ischemia (each lasting 60 seconds) were applied either before (preRIC, n:11), or during (perRIC, n:12) or immediately after (postRIC, n:9) 20 minutes of arm ischemia. The microvascular flow of arm was assessed before and after ischemia using iontophoresis of the endothelium-derived nitric oxide (NO) releaser acetylcholine (ACh) and the endothelium-independent NO donor sodium nitroprusside (SNP). Changes in microvascular blood flow were measured using Laser Doppler imaging. The plasma level of biomarkers related to endothelial function such as nitric oxide (NO), asymmetric dimethylarginine (ADMA), total antioxidant capacity (TAC) and hydrogen sulphide (H2S) were measured. RESULTS: No difference was determined between the groups in terms of age, BMI or blood biochemicals reflecting cardiovascular status. ACh caused a rise in microvascular blood flow in a charge dependent manner. The ACh-induced flow increase was not significantly depressed by ischemia and not affected by any of the types of RIC in the study subjects. The increase in SNP-induced microvascular flow was significantly decreased in the ISC, perRIC and postRIC groups, but not in the preRIC group. Plasma levels of NO, ADMA, TAC and H2S were not changed by ischemia and RIC. CONCLUSION: These results suggested that microvascular perfusion of human forearm skin was elevated by either endothelium or drug-derived NO. The effect of ischemia and RIC on NO-induced flow increase was affected differently by different applications in the healthy young individuals. These complicated results are taken into consideration in experimental and therapeutic interventions.
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Hemodinâmica/fisiologia , Isquemia/fisiopatologia , Microcirculação/genética , Adulto , Humanos , Masculino , Adulto JovemRESUMO
The pathophysiology of sporadic Alzheimer's disease (AD) remains uncertain. Along with brain amyloid-ß (Aß) deposits and neurofibrillary tangles, cerebrovascular dysfunction is increasingly recognized as fundamental to the pathogenesis of AD. Using an experimental model of limb ischemia in transgenic APPPS1 mice, a model of AD (AD mice), we showed that microvascular impairment also extends to the peripheral vasculature in AD. At D70 following femoral ligation, we evidenced a significant decrease in cutaneous blood flow (- 29%, P < 0.001), collateral recruitment (- 24%, P < 0.001), capillary density (- 22%; P < 0.01) and arteriole density (- 28%; P < 0.05) in hind limbs of AD mice compared to control WT littermates. The reactivity of large arteries was not affected in AD mice, as confirmed by unaltered size, and vasoactive responses to pharmacological stimuli of the femoral artery. We identified blood as the only source of Aß in the hind limb; thus, circulating Aß is likely responsible for the impairment of peripheral vasculature repair mechanisms. The levels of the majority of pro-angiogenic mediators were not significantly modified in AD mice compared to WT mice, except for TGF-ß1 and PlGF-2, both of which are involved in vessel stabilization and decreased in AD mice (P = 0.025 and 0.019, respectively). Importantly, endothelin-1 levels were significantly increased, while those of nitric oxide were decreased in the hind limb of AD mice (P < 0.05). Our results suggest that vascular dysfunction is a systemic disorder in AD mice. Assessment of peripheral vascular function may therefore provide additional tools for early diagnosis and management of AD.
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Doença de Alzheimer/fisiopatologia , Membro Posterior/fisiopatologia , Isquemia/fisiopatologia , Doenças Vasculares Periféricas/fisiopatologia , Doença de Alzheimer/sangue , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Arteríolas/metabolismo , Arteríolas/fisiopatologia , Capilares/metabolismo , Capilares/fisiopatologia , Modelos Animais de Doenças , Endotelina-1/sangue , Artéria Femoral/metabolismo , Artéria Femoral/fisiopatologia , Membro Posterior/irrigação sanguínea , Humanos , Isquemia/genética , Camundongos , Camundongos Transgênicos , Microcirculação/genética , Óxido Nítrico/sangue , Doenças Vasculares Periféricas/sangue , Doenças Vasculares Periféricas/genética , Fator de Crescimento Placentário/sangue , Fator de Crescimento Transformador beta1/sangueRESUMO
BACKGROUND: Quantitative Imaging of microcirculatory disorders is challenging. OBJECTIVE: To investigate the feasibility of 2D Fluorescence Optical Imaging (FOI) for characterization and quantification of microcirculatory disorders in peripheral arterial occlusive disease (PAOD) of the upper extremity. METHODS: 9 patients with various clinical presentations of PAOD of the upper extremity were included. Quantitative analysis of both hands was performed by assessing the fluorescence intensity of Indocyanine Green (ICG) dynamically over a time period of 360 seconds. Analysis of the signal intensity within multiple regions of both hands was calculated and time-dependent perfusion curves for each region of interest were plotted over time. RESULTS: Compared to the healthy, vascular non-impaired segments, pathological segments with an impaired tissue perfusion were identified through a decreased rate of early tissue enhancement (pâ=â0.02) and increased signal intensity of the optical perfusion agent per second (pâ<â0.001). The affected segments showed a decreased maximum signal intensity and a prolonged interval to reach the maximum signal intensity (time to peak). CONCLUSION: 2D FOI allows quantitative assessment of the peripheral microcirculation in various vascular pathophysiologies and is able to detect the impaired tissue perfusion in patients with vascular disorders of the upper extremity.
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Fluorescência , Microcirculação/genética , Imagem Óptica/métodos , Doença Arterial Periférica/fisiopatologia , Extremidade Superior/inervação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Extremidade Superior/patologiaRESUMO
Precise diagnosis of antibody-mediated rejection (AMR) in cardiac allograft endomyocardial biopsies (EMBs) remains challenging. This study assessed molecular diagnostics in human EMBs with AMR. A set of 34 endothelial, natural killer cell and inflammatory genes was quantified in 106 formalin-fixed, paraffin-embedded EMBs classified according to 2013 International Society for Heart and Lung Transplantation (ISHLT) criteria. The gene set expression was compared between ISHLT diagnoses and correlated with donor-specific antibody (DSA), endothelial injury by electron microscopy (EM) and prognosis. Findings were validated in an independent set of 57 EMBs. In the training set (n = 106), AMR cases (n = 70) showed higher gene set expression than acute cellular rejection (ACR; n = 21, p < 0.001) and controls (n = 15, p < 0.0001). Anti-HLA DSA positivity was associated with higher gene set expression (p = 0.01). Endothelial injury by electron microscopy strongly correlated with gene set expression, specifically in AMR cases (r = 0.62, p = 0.002). Receiver operating characteristic curve analysis for diagnosing AMR showed greater accuracy with gene set expression (area under the curve [AUC] = 79.88) than with DSA (AUC = 70.47) and C4d (AUC = 70.71). In AMR patients (n = 17) with sequential biopsies, increasing gene set expression was associated with inferior prognosis (p = 0.034). These findings were confirmed in the validation set. In conclusion, biopsy-based molecular assessment of antibody-mediated microcirculation injury has the potential to improve diagnosis of AMR in human cardiac transplants.