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1.
Nature ; 590(7846): 457-462, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33568812

RESUMO

In contrast to nearly all other tissues, the anatomy of cell differentiation in the bone marrow remains unknown. This is owing to a lack of strategies for examining myelopoiesis-the differentiation of myeloid progenitors into a large variety of innate immune cells-in situ in the bone marrow. Such strategies are required to understand differentiation and lineage-commitment decisions, and to define how spatial organizing cues inform tissue function. Here we develop approaches for imaging myelopoiesis in mice, and generate atlases showing the differentiation of granulocytes, monocytes and dendritic cells. The generation of granulocytes and dendritic cells-monocytes localizes to different blood-vessel structures known as sinusoids, and displays lineage-specific spatial and clonal architectures. Acute systemic infection with Listeria monocytogenes induces lineage-specific progenitor clusters to undergo increased self-renewal of progenitors, but the different lineages remain spatially separated. Monocyte-dendritic cell progenitors (MDPs) map with nonclassical monocytes and conventional dendritic cells; these localize to a subset of blood vessels expressing a major regulator of myelopoiesis, colony-stimulating factor 1 (CSF1, also known as M-CSF)1. Specific deletion of Csf1 in endothelium disrupts the architecture around MDPs and their localization to sinusoids. Subsequently, there are fewer MDPs and their ability to differentiate is reduced, leading to a loss of nonclassical monocytes and dendritic cells during both homeostasis and infection. These data indicate that local cues produced by distinct blood vessels are responsible for the spatial organization of definitive blood cell differentiation.


Assuntos
Rastreamento de Células/métodos , Células Mieloides/citologia , Mielopoese , Coloração e Rotulagem/métodos , Animais , Atlas como Assunto , Vasos Sanguíneos/citologia , Vasos Sanguíneos/metabolismo , Linhagem da Célula , Autorrenovação Celular , Células Dendríticas/citologia , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Feminino , Granulócitos/citologia , Listeria monocytogenes/patogenicidade , Listeriose/microbiologia , Fator Estimulador de Colônias de Macrófagos/deficiência , Fator Estimulador de Colônias de Macrófagos/genética , Fator Estimulador de Colônias de Macrófagos/metabolismo , Masculino , Camundongos , Monócitos/citologia , Células Mieloides/metabolismo
2.
Int J Mol Sci ; 22(2)2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-33466887

RESUMO

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


Assuntos
Células Endoteliais/metabolismo , Microdomínios da Membrana/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Anticolesterolemiantes/farmacologia , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/fisiologia , Bovinos , Células Cultivadas , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Microdomínios da Membrana/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Estabilidade Proteica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Sinvastatina/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo
3.
Int J Mol Sci ; 22(2)2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33430201

RESUMO

Endothelial cells (ECs) lining the blood vessels are important players in many biological phenomena but are crucial in hypoxia-dependent diseases where their deregulation contributes to pathology. On the other hand, processes mediated by ECs, such as angiogenesis, vessel permeability, interactions with cells and factors circulating in the blood, maintain homeostasis of the organism. Understanding the diversity and heterogeneity of ECs in different tissues and during various biological processes is crucial in biomedical research to properly develop our knowledge on many diseases, including cancer. Here, we review the most important aspects related to ECs' heterogeneity and list the available in vitro tools to study different angiogenesis-related pathologies. We focus on the relationship between functions of ECs and their organo-specificity but also point to how the microenvironment, mainly hypoxia, shapes their activity. We believe that taking into account the specific features of ECs that are relevant to the object of the study (organ or disease state), especially in a simplified in vitro setting, is important to truly depict the biology of endothelium and its consequences. This is possible in many instances with the use of proper in vitro tools as alternative methods to animal testing.


Assuntos
Hipóxia Celular/genética , Microambiente Celular/genética , Células Endoteliais/citologia , Neovascularização Fisiológica/genética , Vasos Sanguíneos/crescimento & desenvolvimento , Vasos Sanguíneos/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Células-Tronco Pluripotentes Induzidas/citologia
4.
Methods Mol Biol ; 2206: 205-222, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32754820

RESUMO

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


Assuntos
Angiografia/métodos , Vasos Sanguíneos/fisiologia , Peixe-Zebra/fisiologia , Animais , Vasos Sanguíneos/metabolismo , Morfolinos/metabolismo , Neovascularização Fisiológica/fisiologia , Fenótipo , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/metabolismo
5.
Methods Mol Biol ; 2206: 223-232, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32754821

RESUMO

Exiting developments in tissue engineering and new insights in stem cell biology have led to new possible strategies for the regeneration of damaged tissues in the oral cavity. The regeneration of the pulp-dentin complex regeneration in particular, has drawn the attention of many researchers because of the high clinical needs. While it is still important to perform in vitro research using a wide variety of cells, scaffolds and growth factors, it is also critical to have a reliable animal model for preclinical trials. In this chapter, we describe a mouse model in which a scaffold resembling a tooth containing dental pulp cells is implanted subcutaneously. We also describe which histological stainings could be used to examine blood vessel formation and the regeneration of the pulp-dentin complex.


Assuntos
Polpa Dentária/citologia , Regeneração/fisiologia , Pele/citologia , Animais , Vasos Sanguíneos/citologia , Vasos Sanguíneos/metabolismo , Polpa Dentária/metabolismo , Dentina/metabolismo , Camundongos , Camundongos Nus , Camundongos SCID , Modelos Animais , Pele/metabolismo , Células-Tronco/citologia , Engenharia Tecidual/métodos , Tecidos Suporte
6.
Microvasc Res ; 133: 104096, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33058899

RESUMO

OBJECTIVE: To examine the contributions of calcium-activated K+ (KCa) channels and nitric oxide synthase (NOS) to adenosine triphosphate (ATP)-induced cutaneous vasodilation in healthy older adults. METHODS: In eleven older adults (69 ± 2 years, 5 females), cutaneous vascular conductance, normalized to maximum vasodilation (%CVCmax) was assessed at four dorsal forearm skin sites that were continuously perfused with either 1) lactated Ringer solution (Control), 2) 50 mM tetraethylammonium (TEA, KCa channel blocker), 3) 10 mM Nω-nitro-L-arginine (L-NNA, NOS inhibitor), or 4) combined 50 mM TEA +10 mM L-NNA, via microdialysis. Local skin temperature was fixed at 33 °C at all sites with local heaters throughout the protocol while the cutaneous vasodilator response was assessed during coadministration of ATP (0.03, 0.3, 3, 30, 300 mM; 20 min per dose), followed by 50 mM sodium nitroprusside and local skin heating to 43 °C to achieve maximum vasodilation (20-30 min). RESULTS: Blockade of KCa channels blunted %CVCmax relative to Control from 0.3 to 300 mM ATP (All P < 0.05). A similar response was observed for the combined KCa channel blockade and NOS inhibition site from 3 to 300 mM ATP (All P < 0.05). Conversely, NOS inhibition alone did not influence %CVCmax across all ATP doses (All P > 0.05). CONCLUSION: In healthy older adults, KCa channels play an important role in modulating ATP-induced cutaneous vasodilation, while the NOS contribution to this response is negligible.


Assuntos
Trifosfato de Adenosina/farmacologia , Vasos Sanguíneos/efeitos dos fármacos , Canais de Potássio Cálcio-Ativados/metabolismo , Pele/irrigação sanguínea , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Fatores Etários , Idoso , Vasos Sanguíneos/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Masculino , Microdiálise , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Canais de Potássio Cálcio-Ativados/antagonistas & inibidores , Transdução de Sinais
7.
PLoS One ; 15(10): e0240035, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33031376

RESUMO

In the post-natal mammalian brain perivascular astrocytes (PAs) ensheath blood vessels to regulate their unique permeability properties known as the blood-brain barrier (BBB). Very little is known about PA-expressed genes and signaling pathways that mediate contact and communication with endothelial cells (ECs) to regulate BBB physiology. This is due, in part, to lack of suitable models to distinguish PAs from other astrocyte sub-populations in the brain. To decipher the unique biology of PAs, we used in vivo gene knock-in technology to fluorescently label these cells in the adult mouse brain followed by fractionation and quantitative single cell RNA sequencing. In addition, PAs and non-PAs were also distinguished with transgenic fluorescent reporters followed by gene expression comparisons using bulk RNA sequencing. These efforts have identified several genes and pathways in PAs with potential roles in contact and communication with brain ECs. These genes encode various extracellular matrix (ECM) proteins and adhesion receptors, secreted growth factors, and intracellular signaling enzymes. Collectively, our experimental data reveal a set of genes that are expressed in PAs with putative roles in BBB physiology.


Assuntos
Astrócitos/metabolismo , Vasos Sanguíneos/metabolismo , Animais , Astrócitos/citologia , Vasos Sanguíneos/citologia , Barreira Hematoencefálica/metabolismo , Encéfalo/citologia , Encéfalo/patologia , Comunicação Celular/genética , Células Cultivadas , Análise por Conglomerados , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Camundongos , Análise de Sequência de RNA , Análise de Célula Única , Transcriptoma
8.
Proc Natl Acad Sci U S A ; 117(40): 24964-24973, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-32958663

RESUMO

Influenza A virus (IAV) infection during pregnancy causes severe maternal and perinatal complications, despite a lack of vertical transmission of IAV across the placenta. Here, we demonstrate a significant alteration in the maternal vascular landscape that underpins the maternal and downstream fetal pathology to IAV infection in mice. In IAV infection of nonpregnant mice, the local lung inflammatory response was contained to the lungs and was self-resolving, whereas in pregnant mice, virus dissemination to major maternal blood vessels, including the aorta, resulted in a peripheral "vascular storm," with elevated proinflammatory and antiviral mediators and the influx of Ly6Clow and Ly6Chigh monocytes, plus neutrophils and T cells. This vascular storm was associated with elevated levels of the adhesion molecules ICAM and VCAM and the pattern-recognition receptors TLR7 and TLR9 in the vascular wall, resulting in profound vascular dysfunction. The sequalae of this IAV-driven vascular storm included placental growth retardation and intrauterine growth restriction, evidence of placental and fetal brain hypoxia, and increased circulating cell free fetal DNA and soluble Flt1. In contrast, IAV infection in nonpregnant mice caused no obvious alterations in endothelial function or vascular inflammation. Therefore, IAV infection during pregnancy drives a significant systemic vascular alteration in pregnant dams, which likely suppresses critical blood flow to the placenta and fetus. This study in mice provides a fundamental mechanistic insight and a paradigm into how an immune response to a respiratory virus, such as IAV, is likely to specifically drive maternal and fetal pathologies during pregnancy.


Assuntos
Imunidade Adaptativa/genética , Imunidade Inata/genética , Inflamação/genética , Vírus da Influenza A/genética , Animais , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/patologia , Feminino , Feto/imunologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Inflamação/virologia , Vírus da Influenza A/patogenicidade , Influenza Humana/genética , Influenza Humana/imunologia , Influenza Humana/virologia , Glicoproteínas de Membrana/genética , Camundongos , Monócitos/metabolismo , Monócitos/patologia , Placenta/irrigação sanguínea , Placenta/imunologia , Placenta/virologia , Gravidez , Linfócitos T/imunologia , Linfócitos T/virologia , Receptor 7 Toll-Like/genética , Receptor Toll-Like 9/genética
9.
Nat Commun ; 11(1): 3866, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737287

RESUMO

Upon severe head injury (HI), blood vessels of the meninges and brain parenchyma are inevitably damaged. While limited vascular regeneration of the injured brain has been studied extensively, our understanding of meningeal vascular regeneration following head injury is quite limited. Here, we identify key pathways governing meningeal vascular regeneration following HI. Rapid and complete vascular regeneration in the meninges is predominantly driven by VEGFR2 signaling. Substantial increase of VEGFR2 is observed in both human patients and mouse models of HI, and endothelial cell-specific deletion of Vegfr2 in the latter inhibits meningeal vascular regeneration. We further identify the facilitating, stabilizing and arresting roles of Tie2, PDGFRß and Dll4 signaling, respectively, in meningeal vascular regeneration. Prolonged inhibition of this angiogenic process following HI compromises immunological and stromal integrity of the injured meninges. These findings establish a molecular framework for meningeal vascular regeneration after HI, and may guide development of wound healing therapeutics.


Assuntos
Traumatismos Craniocerebrais/genética , Células Endoteliais/metabolismo , Neovascularização Fisiológica/genética , Regeneração/genética , Transdução de Sinais/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/patologia , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Circulação Cerebrovascular , Traumatismos Craniocerebrais/metabolismo , Traumatismos Craniocerebrais/patologia , Modelos Animais de Doenças , Células Endoteliais/patologia , Regulação da Expressão Gênica/genética , Humanos , Macrófagos/metabolismo , Macrófagos/patologia , Meninges/lesões , Meninges/metabolismo , Camundongos , Camundongos Knockout , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptor TIE-2/genética , Receptor TIE-2/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Cicatrização/genética
10.
Mol Syst Biol ; 16(7): e9610, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32715618

RESUMO

The novel SARS-coronavirus 2 (SARS-CoV-2) poses a global challenge on healthcare and society. For understanding the susceptibility for SARS-CoV-2 infection, the cell type-specific expression of the host cell surface receptor is necessary. The key protein suggested to be involved in host cell entry is angiotensin I converting enzyme 2 (ACE2). Here, we report the expression pattern of ACE2 across > 150 different cell types corresponding to all major human tissues and organs based on stringent immunohistochemical analysis. The results were compared with several datasets both on the mRNA and protein level. ACE2 expression was mainly observed in enterocytes, renal tubules, gallbladder, cardiomyocytes, male reproductive cells, placental trophoblasts, ductal cells, eye, and vasculature. In the respiratory system, the expression was limited, with no or only low expression in a subset of cells in a few individuals, observed by one antibody only. Our data constitute an important resource for further studies on SARS-CoV-2 host cell entry, in order to understand the biology of the disease and to aid in the development of effective treatments to the viral infection.


Assuntos
Peptidil Dipeptidase A/metabolismo , Sistema Respiratório/metabolismo , Betacoronavirus , Vasos Sanguíneos/metabolismo , Túnica Conjuntiva/metabolismo , Enterócitos/metabolismo , Feminino , Vesícula Biliar/metabolismo , Interações entre Hospedeiro e Microrganismos , Humanos , Imuno-Histoquímica , Túbulos Renais Proximais/metabolismo , Masculino , Espectrometria de Massas , Miócitos Cardíacos/metabolismo , Especificidade de Órgãos , Peptidil Dipeptidase A/genética , Placenta/metabolismo , Gravidez , RNA-Seq , Análise de Célula Única , Testículo/metabolismo
11.
PLoS One ; 15(7): e0235799, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32658897

RESUMO

ATP-dependent chromatin-remodeling complexes epigenetically modulate transcription of target genes to impact a variety of developmental processes. Our lab previously demonstrated that CHD4-a central ATPase and catalytic enzyme of the NuRD chromatin-remodeling complex-plays an important role in murine embryonic endothelial cells by transcriptionally regulating vascular integrity at midgestation. Since NuRD complexes can incorporate the ATPase CHD3 as an alternative to CHD4, we questioned whether the CHD3 enzyme likewise modulates vascular development or integrity. We generated a floxed allele of Chd3 but saw no evidence of lethality or vascular anomalies when we deleted it in embryonic endothelial cells in vivo (Chd3ECKO). Furthermore, double-deletion of Chd3 and Chd4 in embryonic endothelial cells (Chd3/4ECKO) did not dramatically alter the timing and severity of embryonic phenotypes seen in Chd4ECKO mutants, indicating that CHD3 does not play a cooperative role with CHD4 in early vascular development. However, excision of Chd3 at the epiblast stage of development with a Sox2-Cre line allowed us to generate global heterozygous Chd3 mice (Chd3Δ/+), which were subsequently intercrossed and revealed partial lethality of Chd3Δ/Δ mutants prior to weaning. Tissues from surviving Chd3Δ/Δ mutants helped us confirm that CHD3 was efficiently deleted in these animals and that CHD3 is highly expressed in the gonads and brains of adult wildtype mice. Therefore, Chd3-flox mice will be beneficial for future studies about roles for this chromatin-remodeling enzyme in viable embryonic development and in gonadal and brain physiology.


Assuntos
Vasos Sanguíneos/embriologia , Proteínas de Ligação a DNA/genética , Embrião de Mamíferos/embriologia , Animais , Vasos Sanguíneos/metabolismo , Montagem e Desmontagem da Cromatina , Proteínas de Ligação a DNA/metabolismo , Perda do Embrião/genética , Perda do Embrião/metabolismo , Embrião de Mamíferos/metabolismo , Feminino , Deleção de Genes , Regulação da Expressão Gênica no Desenvolvimento , Masculino , Camundongos
12.
J Thromb Thrombolysis ; 50(3): 567-579, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32627126

RESUMO

After the emergence of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome Coronavirus (MERS-CoV) in the last two decades, the world is facing its new challenge in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic with unprecedented global response. With the expanding domain of presentations in COVID-19 patients, the full range of manifestations is yet to unfold. The classical clinical symptoms for SARS-CoV-2 affected patients are dry cough, high fever, dyspnoea, lethal pneumonia whereas many patients have also been found to be associated with a few additional signs and clinical manifestations of isolated vasculopathy. Albeit a deep and profound knowledge has been gained on the clinical features and management of COVID-19, less clear association has been provided on SARS-CoV-2 mediated direct or indirect vasculopathy and its possible correlation with disease prognosis. The accumulative evidences suggest that novel coronavirus, apart from its primary respiratory confinement, may also invade vascular endothelial cells of several systems including cerebral, cardio-pulmonary as well as renal microvasculature, modulating multiple visceral perfusion indices. Here we analyse the phylogenetic perspective of SARS-CoV-2 along with other strains of ß-coronaviridae from a standpoint of vasculopathic derangements. Based on the existing case reports, literature and open data bases, we also analyse the differential pattern of vasculopathy related changes in COVID-19 positive patients. Besides, we debate the need of modulation in clinical approach from a hemodynamical point of view, as a measure towards reducing disease transmission, morbidity and mortality in SARS-CoV-2 affected patients.


Assuntos
Betacoronavirus/patogenicidade , Vasos Sanguíneos/virologia , Infecções por Coronavirus/virologia , Pneumonia Viral/virologia , Doenças Vasculares/virologia , Animais , Betacoronavirus/genética , Betacoronavirus/imunologia , Coagulação Sanguínea , Vasos Sanguíneos/imunologia , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/fisiopatologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/fisiopatologia , Citocinas/metabolismo , Hemodinâmica , Interações Hospedeiro-Patógeno , Humanos , Mediadores da Inflamação/metabolismo , Pandemias , Filogenia , Pneumonia Viral/imunologia , Pneumonia Viral/metabolismo , Pneumonia Viral/fisiopatologia , Prognóstico , Medição de Risco , Fatores de Risco , Doenças Vasculares/imunologia , Doenças Vasculares/metabolismo , Doenças Vasculares/fisiopatologia
13.
PLoS One ; 15(7): e0235135, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32628733

RESUMO

BACKGROUND: In patients on hemodialysis (HD), the various chemical elements in the dialysate may influence survival rates. In particular, calcium modifies mineral and bone metabolism and the vascular calcification rate. We studied the influence of the dialysate calcium concentration and the treatments prescribed for mineral bone disease (MBD) on survival. METHODS: All patients in REIN having initiated HD from 2010 to 2013 were classified according to their exposure to the different dialysate calcium concentrations in their dialysis unit. Data on the individual patients' treatments for MBD were extracted from the French national health database. Cox proportional hazard models were used to estimate mortality hazard ratios (HR) associated with time-dependent exposure to dialysate calcium concentrations and MBD therapies, adjusted for comorbidities, laboratory and technical data. RESULTS: Dialysate calcium concentration of 1.5 mmol/L was used by 81% of the dialysis centers in 2010 and in 83% in 2014. Most centers were using several formulas in up to 78% for 3 formulas in 2010 to 86% in 2014. In full adjusted Cox survival analyses, the percentage of calcium >1.5 mmol/L and <1.5 mmol/l by center and the number of formula used per center were not associated with survival. Depending on the daily dose used, the MBD therapies were associated with survival improvement for calcium, native vitamin D, active vitamin D, sevelamer, lanthanum and cinacalcet in the second and third tertiles of dose. CONCLUSION: No influence of the dialysate calcium concentration was evidenced on survival whereas all MBD therapies were associated with a survival improvement depending on the daily dose used.


Assuntos
Osso e Ossos/efeitos dos fármacos , Cálcio/análise , Soluções para Hemodiálise/análise , Sistema de Registros , Diálise Renal , Insuficiência Renal Crônica/terapia , Idoso , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/fisiopatologia , Osso e Ossos/metabolismo , Osso e Ossos/fisiopatologia , Calcinose/epidemiologia , Calcinose/metabolismo , Calcinose/fisiopatologia , Cálcio/administração & dosagem , Cálcio/metabolismo , Cinacalcete/análise , Feminino , França/epidemiologia , Soluções para Hemodiálise/administração & dosagem , Soluções para Hemodiálise/química , Humanos , Lantânio/análise , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/mortalidade , Insuficiência Renal Crônica/fisiopatologia , Sevelamer/análise , Vitamina D/análise , Vitamina D/metabolismo
14.
Nat Commun ; 11(1): 3169, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32576825

RESUMO

Understanding tumor metabolism holds the promise of new insights into cancer biology, diagnosis and treatment. To assess human cancer metabolism, here we report a method to collect intra-operative samples of blood from an artery directly upstream and a vein directly downstream of a brain tumor, as well as samples from dorsal pedal veins of the same patients. After performing targeted metabolomic analysis, we characterize the metabolites consumed and produced by gliomas in vivo by comparing the arterial supply and venous drainage. N-acetylornithine, D-glucose, putrescine, and L-acetylcarnitine are consumed in relatively large amounts by gliomas. Conversely, L-glutamine, agmatine, and uridine 5-monophosphate are produced in relatively large amounts by gliomas. Further we verify that D-2-hydroxyglutarate (D-2HG) is high in venous plasma from patients with isocitrate dehydrogenases1 (IDH1) mutations. Through these paired comparisons, we can exclude the interpatient variation that is present in plasma samples usually taken from the cubital vein.


Assuntos
Biomarcadores Tumorais/sangue , Vasos Sanguíneos/metabolismo , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/metabolismo , Glioma/sangue , Glioma/metabolismo , Metabolômica , Acetilcarnitina/sangue , Adulto , Idoso , Agmatina/sangue , Sangue , Análise Química do Sangue , Glicemia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Feminino , Glioma/diagnóstico por imagem , Glioma/genética , Glucose , Glutamina/sangue , Glutaratos/sangue , Humanos , Isocitrato Desidrogenase/sangue , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Masculino , Pessoa de Meia-Idade , Ornitina/análogos & derivados , Ornitina/sangue , Putrescina/sangue , Uridina Monofosfato/sangue , Adulto Jovem
15.
Vasc Med ; 25(4): 364-377, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32568624

RESUMO

Vascular malformations occur during early vascular development resulting in abnormally formed vessels that can manifest as arterial, venous, capillary or lymphatic lesions, or in combination, and include local tissue overdevelopment. Vascular malformations are largely caused by sporadic somatic gene mutations. This article aims to review and discuss current molecular signaling pathways and therapeutic targets for vascular malformations and to classify vascular malformations according to the molecular pathways involved. A literature review was performed using Embase and Medline. Different MeSH terms were combined for the search strategy, with the aim of encompassing all studies describing the classification, pathogenesis, and treatment of vascular malformations. Major pathways involved in the pathogenesis of vascular malformations are vascular endothelial growth factor (VEGF), Ras/Raf/MEK/ERK, angiopoietin-TIE2, transforming growth factor beta (TGF-ß), and PI3K/AKT/mTOR. These pathways are involved in controlling cellular growth, apoptosis, differentiation, and proliferation, and play a central role in endothelial cell signaling and angiogenesis. Many vascular malformations share similar aberrant molecular signaling pathways with cancers and inflammatory disorders. Therefore, selective anticancer agents and immunosuppressants may be beneficial in treating vascular malformations of specific mutations. The current classification systems of vascular malformations, including the International Society of the Study of Vascular Anomalies (ISSVA) classification, are primarily observational and clinical, and are not based on the molecular pathways involved in the pathogenesis of the condition. Several molecular pathways with potential therapeutic targets have been demonstrated to contribute to the development of various vascular anomalies. Classifying vascular malformations based on their molecular pathogenesis may improve treatment by determining the underlying nature of the condition and their potential therapeutic target.


Assuntos
Vasos Sanguíneos/anormalidades , Mutação , Transdução de Sinais/genética , Terminologia como Assunto , Malformações Vasculares/genética , Vasos Sanguíneos/metabolismo , Predisposição Genética para Doença , Humanos , Fenótipo , Fatores de Risco , Malformações Vasculares/classificação , Malformações Vasculares/metabolismo , Malformações Vasculares/patologia
16.
Am J Physiol Heart Circ Physiol ; 319(2): H271-H281, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32559139

RESUMO

The purpose of this study was to investigate the effect of race and subclinical elevations in blood pressure (i.e., prehypertension) on cutaneous sensory nerve-mediated and nitric oxide (NO)-dependent vasodilation. We recruited participants who self-identified as either non-Hispanic black (n = 16) or non-Hispanic white (n = 16). Within each group, participants were subdivided as either normotensive (n = 8 per group) or prehypertensive (n = 8 per group). Each participant was instrumented with four intradermal microdialysis fibers: 1) control (lactated Ringer's), 2) 5% lidocaine (sensory nerve inhibition), 3) 20 mM Nω-nitro-l-arginine methyl ester (l-NAME) (NO synthase inhibition), and 4) lidocaine + l-NAME. Skin blood flow was assessed via laser-Doppler flowmetry, and each site underwent local heating from 33°C to 39°C. At the plateau, 20 mM l-NAME were infused at control and lidocaine sites to quantify NO-dependent vasodilation. Maximal vasodilation was induced via 54 mM sodium nitroprusside and local heating to 43°C. Data are means ± SD. Sensory nerve-mediated cutaneous vasodilation was reduced in prehypertensive non-Hispanic white (34 ± 7%) and both non-Hispanic black groups (normotensive, 20 ± 9%, prehypertensive, 24 ± 15%) relative to normotensive non-Hispanic whites (54 ± 12%). NO-dependent vasodilation was also reduced in prehypertensive non-Hispanic white (41 ± 7%) and both non-Hispanic black groups (normotensive, 44 ± 7%, prehypertensive, 19 ± 7%) relative to normotensive non-Hispanic whites (60 ± 11%). The decrease in NO-dependent vasodilation in prehypertensive non-Hispanic blacks was further reduced relative to all other groups. These data suggest subclinical increases in blood pressure adversely affect sensory-mediated and NO-dependent vasodilation in both non-Hispanic blacks and whites.NEW & NOTEWORTHY Overt hypertension is known to reduce cutaneous sensory nerve-mediated and nitric oxide (NO)-dependent vasodilation, but the effect of subclinical increases in blood pressure (i.e., prehypertension) is unknown. The combined effect of race and prehypertension is also unknown. In this study, we found that prehypertension reduces cutaneous sensory nerve-mediated and NO-dependent vasodilation in both non-Hispanic white and black populations, with the greatest reductions observed in prehypertensive non-Hispanic blacks.


Assuntos
Pressão Sanguínea , Vasos Sanguíneos/inervação , Vasos Sanguíneos/metabolismo , Células Endoteliais/metabolismo , Óxido Nítrico/metabolismo , Pré-Hipertensão/fisiopatologia , Células Receptoras Sensoriais , Pele/irrigação sanguínea , Vasodilatação , Administração Cutânea , Adolescente , Adulto , Afro-Americanos , Anestésicos Locais/administração & dosagem , Vasos Sanguíneos/efeitos dos fármacos , Estudos de Casos e Controles , Células Endoteliais/efeitos dos fármacos , Inibidores Enzimáticos/administração & dosagem , Grupo com Ancestrais do Continente Europeu , Feminino , Georgia/epidemiologia , Humanos , Masculino , Microdiálise , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Pré-Hipertensão/diagnóstico , Pré-Hipertensão/etnologia , Pré-Hipertensão/metabolismo , Fatores Raciais , Células Receptoras Sensoriais/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vasodilatadores/administração & dosagem , Adulto Jovem
17.
Vasc Health Risk Manag ; 16: 167-180, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32494148

RESUMO

Vascular calcification (VC) is a life-threatening state in chronic kidney disease (CKD). High cardiovascular mortality and morbidity of CKD cases may root from medial VC promoted by hyperphosphatemia. Vascular calcification is an active, highly regulated, and complex biological process that is mediated by genetics, epigenetics, dysregulated form of matrix mineral metabolism, hormones, and the activation of cellular signaling pathways. Moreover, gut microbiome as a source of uremic toxins (eg, phosphate, advanced glycation end products and indoxyl-sulfate) can be regarded as a potential contributor to VC in CKD. Here, an update on different cellular and molecular processes involved in VC in CKD is discussed to elucidate the probable therapeutic pathways in the future.


Assuntos
Vasos Sanguíneos/metabolismo , Rim/metabolismo , Eliminação Renal , Insuficiência Renal Crônica/complicações , Calcificação Vascular/etiologia , Remodelação Vascular , Animais , Vasos Sanguíneos/patologia , Vasos Sanguíneos/fisiopatologia , Humanos , Rim/fisiopatologia , Prognóstico , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/mortalidade , Insuficiência Renal Crônica/fisiopatologia , Fatores de Risco , Calcificação Vascular/metabolismo , Calcificação Vascular/mortalidade , Calcificação Vascular/fisiopatologia
18.
Nutr Metab Cardiovasc Dis ; 30(6): 889-895, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32409274

RESUMO

AIMS: Kisspeptin-10 (KP-10), a potent vasoconstrictor and inhibitor of angiogenesis, and its receptor, GPR54, have currently received much attention with respect to atherosclerosis, since both KP-10 and GPR54 are expressed at high levels in atheromatous plaques and restenotic lesions after wire-injury. The present review introduces the emerging roles of the KP-10/GPR54 system in atherosclerosis. DATA SYNTHESIS: KP-10 suppresses migration and proliferation of human umbilical vein endothelial cells (HUVECs), and induces senescence in HUVECs. KP-10 increases adhesion of human monocytes to HUVECs. KP-10 also stimulates expression of interleukin-6, tumor necrosis factor-α, monocyte chemotactic protein-1, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin genes in HUVECs. KP-10 enhances oxidized low-density lipoprotein-induced foam cell formation associated with upregulation of CD36 and acyl-coenzyme A: cholesterol acyltransferase-1 in human monocyte-derived macrophages. In human aortic smooth muscle cells, KP-10 suppresses angiotensin II-induced migration and proliferation, however, it enhances apoptosis and activities of matrix metalloproteinase (MMP)-2 and MMP-9 by upregulation of extracellular signal-regulated kinase 1/2, p38, Bax, and caspase-3. Four-week-infusion of KP-10 into Apoe-/- mice accelerates development of aortic atherosclerotic lesions with increased monocyte/macrophage infiltration and vascular inflammation, also, it decreases intraplaque vascular smooth muscle cell content. Proatherosclerotic effects of endogenous and exogenous KP-10 were completely attenuated upon infusion of P234, a GPR54 antagonist, in Apoe-/- mice. CONCLUSION: These findings suggest that KP-10 may contribute to acceleration of progression and to the instability of atheromatous plaques, leading to rupture of plaques. This GPR54 antagonist may be useful for the prevention and treatment of atherosclerosis. Thus, the KP-10/GPR54 system may serve as a novel therapeutic target for atherosclerotic diseases.


Assuntos
Aterosclerose/metabolismo , Vasos Sanguíneos/metabolismo , Kisspeptinas/metabolismo , Placa Aterosclerótica , Receptores de Kisspeptina-1/metabolismo , Animais , Apoptose , Aterosclerose/tratamento farmacológico , Aterosclerose/patologia , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/patologia , Fármacos Cardiovasculares/uso terapêutico , Movimento Celular , Proliferação de Células , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Humanos , Macrófagos/metabolismo , Macrófagos/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Agregação Plaquetária , Receptores de Kisspeptina-1/antagonistas & inibidores , Transdução de Sinais
19.
PLoS One ; 15(4): e0231962, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32324828

RESUMO

Vascular deficits are a fundamental contributing factor of diabetes-associated diseases. Although previous studies have demonstrated that the pro-angiogenic phase of wound healing is blunted in diabetes, a comprehensive understanding of the mechanisms that regulate skin revascularization and capillary stabilization in diabetic wounds is lacking. Using a mouse model of diabetic wound healing, we performed microCT analysis of the 3-dimensional architecture of the capillary bed. As compared to wild type, vessel surface area, branch junction number, total vessel length, and total branch number were significantly decreased in wounds of diabetic mice as compared to WT mice. Diabetic mouse wounds also had significantly increased capillary permeability and decreased pericyte coverage of capillaries. Diabetic wounds exhibited significant perturbations in the expression of factors that affect vascular regrowth, maturation and stability. Specifically, the expression of VEGF-A, Sprouty2, PEDF, LRP6, Thrombospondin 1, CXCL10, CXCR3, PDGFR-ß, HB-EGF, EGFR, TGF-ß1, Semaphorin3a, Neuropilin 1, angiopoietin 2, NG2, and RGS5 were down-regulated in diabetic wounds. Together, these studies provide novel information about the complexity of the perturbation of angiogenesis in diabetic wounds. Targeting factors responsible for wound resolution and vascular pruning, as well those that affect pericyte recruitment, maturation, and stability may have the potential to improve diabetic skin wound healing.


Assuntos
Vasos Sanguíneos/patologia , Vasos Sanguíneos/fisiopatologia , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/fisiopatologia , Neovascularização Patológica , Cicatrização , Animais , Vasos Sanguíneos/diagnóstico por imagem , Vasos Sanguíneos/metabolismo , Capilares/metabolismo , Capilares/fisiopatologia , Diabetes Mellitus Experimental/diagnóstico por imagem , Diabetes Mellitus Experimental/metabolismo , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Pericitos/patologia , Permeabilidade , Microtomografia por Raio-X
20.
Clin Sci (Lond) ; 134(7): 827-851, 2020 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-32271386

RESUMO

Major shifts in human lifestyle and dietary habits toward sedentary behavior and refined food intake triggered steep increase in the incidence of metabolic disorders including obesity and Type 2 diabetes. Patients with metabolic disease are at a high risk of cardiovascular complications ranging from microvascular dysfunction to cardiometabolic syndromes including heart failure. Despite significant advances in the standards of care for obese and diabetic patients, current therapeutic approaches are not always successful in averting the accompanying cardiovascular deterioration. There is a strong relationship between adipose inflammation seen in metabolic disorders and detrimental changes in cardiovascular structure and function. The particular importance of epicardial and perivascular adipose pools emerged as main modulators of the physiology or pathology of heart and blood vessels. Here, we review the peculiarities of these two fat depots in terms of their origin, function, and pathological changes during metabolic deterioration. We highlight the rationale for pharmacological targeting of the perivascular and epicardial adipose tissue or associated signaling pathways as potential disease modifying approaches in cardiometabolic syndromes.


Assuntos
Adipocinas/antagonistas & inibidores , Tecido Adiposo/efeitos dos fármacos , Anti-Inflamatórios/uso terapêutico , Vasos Sanguíneos/efeitos dos fármacos , Doenças Cardiovasculares/tratamento farmacológico , Mediadores da Inflamação/antagonistas & inibidores , Inflamação/tratamento farmacológico , Pericárdio/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Adipocinas/metabolismo , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Tecido Adiposo/fisiopatologia , Adiposidade/efeitos dos fármacos , Animais , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/patologia , Vasos Sanguíneos/fisiopatologia , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/fisiopatologia , Metabolismo Energético/efeitos dos fármacos , Humanos , Inflamação/metabolismo , Inflamação/patologia , Inflamação/fisiopatologia , Mediadores da Inflamação/metabolismo , Terapia de Alvo Molecular , Pericárdio/metabolismo , Pericárdio/patologia , Pericárdio/fisiopatologia , Transdução de Sinais
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