Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 9 de 9
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Hum Mol Genet ; 2021 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-34476477

RESUMO

The etiology of renal artery stenosis (RAS) and abdominal aortic coarctation (AAC) causing the midaortic syndrome (MAS), often resulting in renovascular hypertension (RVH), remains ill-defined. Neurofibromatosis type 1 (NF-1) is frequently observed in children with RVH. Consecutive pediatric patients (N = 102) presenting with RVH secondary to RAS with and without concurrent AAC were prospectively enrolled in a clinical data base, and blood, saliva, and operative tissue when available, were collected. Among the 102 children were 13 having a concurrent clinical diagnosis of NF-1 (12.5%). Whole exome sequencing was performed for germline variant detection and RNASeq analysis of NF1, MAPK pathway genes, and MCP1 levels were undertaken in five NF-1 stenotic renal arteries, as well as control renal and mesenteric arteries from children with no known vasculopathy or NF-1. In 11 unrelated children with sequencing data, 11 NF1 genetic variants were identified, of which 10 had not been reported in gnomAD. Histologic analysis of NF-1 RAS specimens consistently revealed intimal thickening, disruption of the internal elastic lamina, and medial thinning. Analysis of transcript expression in arterial lesions documented an approximately 5-fold reduction in NF1 expression, confirming heterozygosity, MAPK pathway activation, and increased MCP1 expression. In summary, NF-1 related RVH in children is rare but often severe and progressive and as such, important to recognize. It is associated with histologic and molecular features consistent with an aggressive adverse vascular remodeling process. Further research is necessary to define the mechanisms underlying these findings.

3.
FASEB J ; 35(9): e21824, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34370353

RESUMO

Crosstalk between multiple components underlies the formation of mature vessels. Although the players involved in angiogenesis have been identified, mechanisms underlying the crosstalk between them are still unclear. Using the ex vivo aortic ring assay, we set out to dissect the interactions between two key angiogenic signaling pathways, vascular endothelial growth factor (VEGF) and transforming growth factor ß (TGFß), with members of the lysyl oxidase (LOX) family of matrix modifying enzymes. We find an interplay between VEGF, TGFß, and the LOXs is essential for the formation of mature vascular smooth muscle cells (vSMC)-coated vessels. RNA sequencing analysis further identified an interaction with the endothelin-1 pathway. Our work implicates endothelin-1 downstream of TGFß in vascular maturation and demonstrate the complexity of processes involved in generating vSMC-coated vessels.


Assuntos
Endotelina-1/metabolismo , Neovascularização Patológica/metabolismo , Proteína-Lisina 6-Oxidase/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Diferenciação Celular/fisiologia , Células Cultivadas , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Morfogênese/fisiologia , Miócitos de Músculo Liso/metabolismo , Transdução de Sinais/fisiologia , Fator A de Crescimento do Endotélio Vascular/metabolismo
4.
Nat Commun ; 11(1): 4432, 2020 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-32887874

RESUMO

Spontaneous coronary artery dissection (SCAD) is a non-atherosclerotic cause of myocardial infarction (MI), typically in young women. We undertook a genome-wide association study of SCAD (Ncases = 270/Ncontrols = 5,263) and identified and replicated an association of rs12740679 at chromosome 1q21.2 (Pdiscovery+replication = 2.19 × 10-12, OR = 1.8) influencing ADAMTSL4 expression. Meta-analysis of discovery and replication samples identified associations with P < 5 × 10-8 at chromosome 6p24.1 in PHACTR1, chromosome 12q13.3 in LRP1, and in females-only, at chromosome 21q22.11 near LINC00310. A polygenic risk score for SCAD was associated with (1) higher risk of SCAD in individuals with fibromuscular dysplasia (P = 0.021, OR = 1.82 [95% CI: 1.09-3.02]) and (2) lower risk of atherosclerotic coronary artery disease and MI in the UK Biobank (P = 1.28 × 10-17, HR = 0.91 [95% CI :0.89-0.93], for MI) and Million Veteran Program (P = 9.33 × 10-36, OR = 0.95 [95% CI: 0.94-0.96], for CAD; P = 3.35 × 10-6, OR = 0.96 [95% CI: 0.95-0.98] for MI). Here we report that SCAD-related MI and atherosclerotic MI exist at opposite ends of a genetic risk spectrum, inciting MI with disparate underlying vascular biology.


Assuntos
Anomalias dos Vasos Coronários/genética , Genes Neoplásicos , Infarto do Miocárdio/genética , Doenças Vasculares/congênito , Proteínas ADAMTS/genética , Doenças das Artérias Carótidas/complicações , Doenças das Artérias Carótidas/genética , Cromossomos/genética , Estudos de Coortes , Doença da Artéria Coronariana/genética , Feminino , Displasia Fibromuscular/complicações , Displasia Fibromuscular/genética , Estudo de Associação Genômica Ampla , Humanos , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Masculino , Metanálise como Assunto , Proteínas dos Microfilamentos/genética , Fatores de Risco , Doenças Vasculares/genética
5.
Arterioscler Thromb Vasc Biol ; 40(11): 2686-2699, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32938213

RESUMO

OBJECTIVE: While rare variants in the COL5A1 gene have been associated with classical Ehlers-Danlos syndrome and rarely with arterial dissections, recurrent variants in COL5A1 underlying a systemic arteriopathy have not been described. Monogenic forms of multifocal fibromuscular dysplasia (mFMD) have not been previously defined. Approach and Results: We studied 4 independent probands with the COL5A1 pathogenic variant c.1540G>A, p.(Gly514Ser) who presented with arterial aneurysms, dissections, tortuosity, and mFMD affecting multiple arteries. Arterial medial fibroplasia and smooth muscle cell disorganization were confirmed histologically. The COL5A1 c.1540G>A variant is predicted to be pathogenic in silico and absent in gnomAD. The c.1540G>A variant is on a shared 160.1 kb haplotype with 0.4% frequency in Europeans. Furthermore, exome sequencing data from a cohort of 264 individuals with mFMD were examined for COL5A1 variants. In this mFMD cohort, COL5A1 c.1540G>A and 6 additional relatively rare COL5A1 variants predicted to be deleterious in silico were identified and were associated with arterial dissections (P=0.005). CONCLUSIONS: COL5A1 c.1540G>A is the first recurring variant recognized to be associated with arterial dissections and mFMD. This variant presents with a phenotype reminiscent of vascular Ehlers-Danlos syndrome. A shared haplotype among probands supports the existence of a common founder. Relatively rare COL5A1 genetic variants predicted to be deleterious by in silico analysis were identified in ≈2.7% of mFMD cases, and as they were enriched in patients with arterial dissections, may act as disease modifiers. Molecular testing for COL5A1 should be considered in patients with a phenotype overlapping with vascular Ehlers-Danlos syndrome and mFMD.


Assuntos
Aneurisma Dissecante/genética , Artérias/patologia , Colágeno Tipo V/genética , Síndrome de Ehlers-Danlos/genética , Displasia Fibromuscular/genética , Polimorfismo de Nucleotídeo Único , Adulto , Aneurisma Dissecante/diagnóstico por imagem , Aneurisma Dissecante/patologia , Artérias/diagnóstico por imagem , Síndrome de Ehlers-Danlos/diagnóstico por imagem , Síndrome de Ehlers-Danlos/patologia , Feminino , Displasia Fibromuscular/diagnóstico por imagem , Displasia Fibromuscular/patologia , Predisposição Genética para Doença , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Adulto Jovem
6.
Proc Natl Acad Sci U S A ; 116(47): 23618-23624, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31712416

RESUMO

Endothelial cells (ECs) are highly specialized across vascular beds. However, given their interspersed anatomic distribution, comprehensive characterization of the molecular basis for this heterogeneity in vivo has been limited. By applying endothelial-specific translating ribosome affinity purification (EC-TRAP) combined with high-throughput RNA sequencing analysis, we identified pan EC-enriched genes and tissue-specific EC transcripts, which include both established markers and genes previously unappreciated for their presence in ECs. In addition, EC-TRAP limits changes in gene expression after EC isolation and in vitro expansion, as well as rapid vascular bed-specific shifts in EC gene expression profiles as a result of the enzymatic tissue dissociation required to generate single-cell suspensions for fluorescence-activated cell sorting or single-cell RNA sequencing analysis. Comparison of our EC-TRAP with published single-cell RNA sequencing data further demonstrates considerably greater sensitivity of EC-TRAP for the detection of low abundant transcripts. Application of EC-TRAP to examine the in vivo host response to lipopolysaccharide (LPS) revealed the induction of gene expression programs associated with a native defense response, with marked differences across vascular beds. Furthermore, comparative analysis of whole-tissue and TRAP-selected mRNAs identified LPS-induced differences that would not have been detected by whole-tissue analysis alone. Together, these data provide a resource for the analysis of EC-specific gene expression programs across heterogeneous vascular beds under both physiologic and pathologic conditions.


Assuntos
Células Endoteliais/metabolismo , Regulação da Expressão Gênica , Biossíntese de Proteínas , RNA Mensageiro/metabolismo , Animais , Plaquetas/metabolismo , Encéfalo/irrigação sanguínea , Regulação da Expressão Gênica/efeitos dos fármacos , Sequenciamento de Nucleotídeos em Larga Escala , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Especificidade de Órgãos , Isoformas de Proteínas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas Ribossômicas/metabolismo , Ribossomos/metabolismo , Sensibilidade e Especificidade , Análise de Célula Única , Transgenes , Vísceras/irrigação sanguínea
7.
PLoS One ; 13(8): e0201713, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30157177

RESUMO

Hearing and balance depend upon the precise morphogenesis and mechanosensory function of stereocilia, the specialized structures on the apical surface of sensory hair cells in the inner ear. Previous studies of Grxcr1 mutant mice indicated a critical role for this gene in control of stereocilia dimensions during development. In this study, we analyzed expression of the paralog Grxcr2 in the mouse and evaluated auditory and vestibular function of strains carrying targeted mutations of the gene. Peak expression of Grxcr2 occurs during early postnatal development of the inner ear and GRXCR2 is localized to stereocilia in both the cochlea and in vestibular organs. Homozygous Grxcr2 deletion mutants exhibit significant hearing loss by 3 weeks of age that is associated with developmental defects in stereocilia bundle orientation and organization. Despite these bundle defects, the mechanotransduction apparatus assembles in relatively normal fashion as determined by whole cell electrophysiological evaluation and FM1-43 uptake. Although Grxcr2 mutants do not exhibit overt vestibular dysfunction, evaluation of vestibular evoked potentials revealed subtle defects of the mutants in response to linear accelerations. In addition, reduced Grxcr2 expression in a hypomorphic mutant strain is associated with progressive hearing loss and bundle defects. The stereocilia localization of GRXCR2, together with the bundle pathologies observed in the mutants, indicate that GRXCR2 plays an intrinsic role in bundle orientation, organization, and sensory function in the inner ear during development and at maturity.


Assuntos
Cóclea/citologia , Cóclea/crescimento & desenvolvimento , Glutarredoxinas/metabolismo , Morfogênese , Estereocílios/metabolismo , Sequência de Aminoácidos , Animais , Regulação da Expressão Gênica no Desenvolvimento , Loci Gênicos/genética , Glutarredoxinas/química , Glutarredoxinas/genética , Perda Auditiva/genética , Perda Auditiva/patologia , Humanos , Mecanotransdução Celular , Camundongos , Modelos Moleculares , Mutação , Conformação Proteica , Especificidade da Espécie
8.
Am J Hum Genet ; 86(2): 148-60, 2010 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-20137774

RESUMO

Recessive mutations at the mouse pirouette (pi) locus result in hearing loss and vestibular dysfunction due to neuroepithelial defects in the inner ear. Using a positional cloning strategy, we have identified mutations in the gene Grxcr1 (glutaredoxin cysteine-rich 1) in five independent allelic strains of pirouette mice. We also provide sequence data of GRXCR1 from humans with profound hearing loss suggesting that pirouette is a model for studying the mechanism of nonsyndromic deafness DFNB25. Grxcr1 encodes a 290 amino acid protein that contains a region of similarity to glutaredoxin proteins and a cysteine-rich region at its C terminus. Grxcr1 is expressed in sensory epithelia of the inner ear, and its encoded protein is localized along the length of stereocilia, the actin-filament-rich mechanosensory structures at the apical surface of auditory and vestibular hair cells. The precise architecture of hair cell stereocilia is essential for normal hearing. Loss of function of Grxcr1 in homozygous pirouette mice results in abnormally thin and slightly shortened stereocilia. When overexpressed in transfected cells, GRXCR1 localizes along the length of actin-filament-rich structures at the dorsal-apical surface and induces structures with greater actin filament content and/or increased lengths in a subset of cells. Our results suggest that deafness in pirouette mutants is associated with loss of GRXCR1 function in modulating actin cytoskeletal architecture in the developing stereocilia of sensory hair cells.


Assuntos
Orelha Interna/fisiopatologia , Loci Gênicos/genética , Glutarredoxinas/genética , Mutação/genética , Citoesqueleto de Actina , Alelos , Sequência de Aminoácidos , Animais , Sequência de Bases , Mapeamento Cromossômico , Sequência Conservada , Análise Mutacional de DNA , Evolução Molecular , Feminino , Regulação da Expressão Gênica , Glutarredoxinas/química , Perda Auditiva/genética , Perda Auditiva/fisiopatologia , Humanos , Masculino , Camundongos , Camundongos Mutantes , Dados de Sequência Molecular , Linhagem , Estrutura Terciária de Proteína , Transporte Proteico
9.
Dev Dyn ; 237(4): 941-52, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18330929

RESUMO

The inner ear is a complex organ containing sensory tissue, including hair cells, the development of which is not well understood. Our long-term goal is to discover genes critical for the correct formation and function of the inner ear and its sensory tissue. A novel gene, transmembrane inner ear (Tmie), was found to cause hearing-related disorders when defective in mice and humans. A homologous tmie gene in zebrafish was cloned and its expression characterized between 24 and 51 hours post-fertilization. Embryos injected with morpholinos (MO) directed against tmie exhibited circling swimming behavior (approximately 37%), phenocopying mice with Tmie mutations; semicircular canal formation was disrupted, hair cell numbers were reduced, and maturation of electrically active lateral line neuromasts was delayed. As in the mouse, tmie appears to be required for inner ear development and function in the zebrafish and for hair cell maturation in the vestibular and lateral line systems as well.


Assuntos
Orelha Interna/embriologia , Orelha Interna/fisiologia , Sistema da Linha Lateral/embriologia , Sistema da Linha Lateral/fisiologia , Proteínas de Membrana/genética , Proteínas de Peixe-Zebra/genética , Peixe-Zebra , Sequência de Aminoácidos , Animais , Comportamento Animal/fisiologia , Orelha Interna/anatomia & histologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Sistema da Linha Lateral/anatomia & histologia , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Dados de Sequência Molecular , Morfogênese , Oligonucleotídeos Antissenso/genética , Oligonucleotídeos Antissenso/metabolismo , Alinhamento de Sequência , Natação/fisiologia , Peixe-Zebra/anatomia & histologia , Peixe-Zebra/embriologia , Peixe-Zebra/fisiologia , Proteínas de Peixe-Zebra/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...