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1.
Int J Mol Sci ; 22(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34445337

RESUMO

In fibrotic diseases, myofibroblasts derive from a range of cell types including endothelial-to-mesenchymal transition (EndMT). Increasing evidence suggests that miRNAs are key regulators in biological processes but their profile is relatively understudied in EndMT. In human umbilical vein endothelial cells (HUVEC), EndMT was induced by treatment with TGFß2 and IL1ß. A significant decrease in endothelial markers such as VE-cadherin, CD31 and an increase in mesenchymal markers such as fibronectin were observed. In parallel, miRNA profiling showed that miR-126-3p was down-regulated in HUVECs undergoing EndMT and over-expression of miR-126-3p prevented EndMT, maintaining CD31 and repressing fibronectin expression. EndMT was investigated using lineage tracing with transgenic Cdh5-Cre-ERT2; Rosa26R-stop-YFP mice in two established models of fibrosis: cardiac ischaemic injury and kidney ureteric occlusion. In both cardiac and kidney fibrosis, lineage tracing showed a significant subpopulation of endothelial-derived cells expressed mesenchymal markers, indicating they had undergone EndMT. In addition, miR-126-3p was restricted to endothelial cells and down-regulated in murine fibrotic kidney and heart tissue. These findings were confirmed in patient kidney biopsies. MiR-126-3p expression is restricted to endothelial cells and is down-regulated during EndMT. Over-expression of miR-126-3p reduces EndMT, therefore, it could be considered for miRNA-based therapeutics in fibrotic organs.


Assuntos
Transdiferenciação Celular/genética , Rim/patologia , MicroRNAs/fisiologia , Miocárdio/patologia , Animais , Células Cultivadas , Células Endoteliais/patologia , Células Endoteliais/fisiologia , Fibrose/genética , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Células Endoteliais da Veia Umbilical Humana/fisiologia , Humanos , Rim/metabolismo , Células-Tronco Mesenquimais/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Miofibroblastos/metabolismo , Miofibroblastos/patologia
2.
FASEB J ; 35(5): e21604, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33913566

RESUMO

Myocardial infarction leads to a rapid innate immune response that is ultimately required for repair of damaged heart tissue. We therefore examined circulating monocyte dynamics immediately after reperfusion of the culprit coronary vessel in STEMI patients to determine whether this correlated with level of cardiac injury. A mouse model of cardiac ischemia/reperfusion injury was subsequently used to establish the degree of monocyte margination to the coronary vasculature that could potentially contribute to the drop in circulating monocytes. We retrospectively analyzed blood samples from 51 STEMI patients to assess the number of non-classical (NC), classical, and intermediate monocytes immediately following primary percutaneous coronary intervention. Classical and intermediate monocytes showed minimal change. On the other hand, circulating numbers of NC monocytes fell by approximately 50% at 90 minutes post-reperfusion. This rapid decrease in NC monocytes was greatest in patients with the largest infarct size (P < .05) and correlated inversely with left ventricular function (r = 0.41, P = .04). The early fall in NC monocytes post-reperfusion was confirmed in a second prospective study of 13 STEMI patients. Furthermore, in a mouse cardiac ischemia model, there was significant monocyte adhesion to coronary vessel endothelium at 2 hours post-reperfusion pointing to a specific and rapid vessel margination response to cardiac injury. In conclusion, rapid depletion of NC monocytes from the circulation in STEMI patients following coronary artery reperfusion correlates with the level of acute cardiac injury and involves rapid margination to the coronary vasculature.


Assuntos
Traumatismos Cardíacos/sangue , Traumatismos Cardíacos/patologia , Monócitos/patologia , Infarto do Miocárdio com Supradesnível do Segmento ST/complicações , Animais , Feminino , Traumatismos Cardíacos/etiologia , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos
3.
Angiogenesis ; 23(4): 559-566, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32506200

RESUMO

INTRODUCTION: Endoglin (ENG) forms a receptor complex with ALK1 in endothelial cells (ECs) to promote BMP9/10 signalling. Loss of function mutations in either ENG or ALK1 genes lead to the inherited vascular disorder hereditary haemorrhagic telangiectasia (HHT), characterised by arteriovenous malformations (AVMs). However, the vessel-specific role of ENG and ALK1 proteins in protecting against AVMs is unclear. For example, AVMs have been described to initiate in arterioles, whereas ENG is predominantly expressed in venous ECs. To investigate whether ENG has any arterial involvement in protecting against AVM formation, we specifically depleted the Eng gene in venous and capillary endothelium whilst maintaining arterial expression, and investigated how this affected the incidence and location of AVMs in comparison with pan-endothelial Eng knockdown. METHODS: Using the mouse neonatal retinal model of angiogenesis, we first established the earliest time point at which Apj-Cre-ERT2 activity was present in venous and capillary ECs but absent from arterial ECs. We then compared the incidence of AVMs following pan-endothelial or venous/capillary-specific ENG knockout. RESULTS: Activation of Apj-Cre-ERT2 with tamoxifen from postnatal day (P) 5 ensured preservation of arterial ENG protein expression. Specific loss of ENG expression in ECs of veins and capillaries led to retinal AVMs at a similar frequency to pan-endothelial loss of ENG. AVMs occurred in the proximal as well as the distal part of the retina consistent with a defect in vascular remodelling during maturation of the vasculature. CONCLUSION: Expression of ENG is not required in arterial ECs to protect against AVM formation.

5.
J Invest Surg ; 33(6): 514-519, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30644772

RESUMO

Introduction: Colorectal cancer (CRC) is the second commonest malignancy related death in Western Europe with incidence increasing in young adults. 31% of UK patients with CRC present as emergencies. We compare the incidence, characteristics, management and outcomes in two cohorts presenting as CRC emergencies; under-50 and over-50 years old. Materials and Methods: Retrospective analysis was performed on 322 patients with emergency presentations of CRC over a 9-year period (January 2005-December 2013, West Suffolk Hospital, UK). Data were analyzed for demographics, symptoms, investigations, stage, grade, genetics, tumor location, management, and mortality. Results: 300 patients over 50 years old presented with CRC emergencies; 153 women (51%):147 men (49%); median age 77 years (interquartile range: 67-84). 22 patients under 50-years-old; 12 women (55%):10 men (45%); median age 43 years ([Interquartile Range (IQR)]: 35-46 years). Bowel obstruction was less common in under-50s (18.2% vs. 40.7%; p = 0.04). No over-50s had a positive family history for CRC; 7 under-50s did. A higher proportion of under-50s presented with Dukes A carcinomas (14.3% vs. 0.4%; p = 0.002), but no difference in other Dukes stages. Surgery was performed in a higher proportion of under-50s (95.5% vs. 77.0%; p = 0.04) and a higher proportion had same day surgery (71.4% vs. 28.1%; p = 0.01). Overall mortality was lower in under-50s (36.4% vs. 64.0%; p = 0.02). No significant differences occurred in in-hospital mortality (4.7% vs. 8.0%; p = 0.55), overall one-year survival (31.8% vs. 41.7%; p = 0.36), or median survival to death or study conclusion (27.1 vs. 19.6 months; p = 0.13). Conclusion: Emergency CRC had comparable outcomes between young and old cohorts, during the study time period. Younger patients were more likely to undergo operative interventions but overall survival was comparable.Our study was limited by the reporting biases intrinsic to retrospective analyses and by a small under-50 sample size. Further large-scale studies are warranted to support observations.


Assuntos
Dor Abdominal/cirurgia , Colectomia/estatística & dados numéricos , Neoplasias Colorretais/cirurgia , Tratamento de Emergência/estatística & dados numéricos , Obstrução Intestinal/cirurgia , Perfuração Intestinal/cirurgia , Dor Abdominal/epidemiologia , Dor Abdominal/etiologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Tomada de Decisão Clínica , Colectomia/métodos , Neoplasias Colorretais/complicações , Neoplasias Colorretais/mortalidade , Tratamento de Emergência/métodos , Feminino , Mortalidade Hospitalar , Humanos , Obstrução Intestinal/epidemiologia , Obstrução Intestinal/etiologia , Perfuração Intestinal/epidemiologia , Perfuração Intestinal/etiologia , Masculino , Anamnese/estatística & dados numéricos , Pessoa de Meia-Idade , Estudos Retrospectivos , Análise de Sobrevida
6.
Circ Res ; 126(2): 243-257, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31805812

RESUMO

RATIONALE: ENG (endoglin) is a coreceptor for BMP (bone morphogenetic protein) 9/10 and is strongly expressed in endothelial cells. Mutations in ENG lead to the inherited vascular disorder hereditary hemorrhagic telangiectasia characterized by local telangiectases and larger arteriovenous malformations (AVMs); but how ENG functions to regulate the adult vasculature is not understood. OBJECTIVE: The goal of the work was to determine how ENG maintains vessel caliber in adult life to prevent AVM formation and thereby protect heart function. METHODS AND RESULTS: Genetic depletion of endothelial Eng in adult mice led to a significant reduction in mean aortic blood pressure. There was no evidence of hemorrhage, anemia, or AVMs in major organs to explain the reduced aortic pressure. However, large AVMs developed in the peripheral vasculature intimately associated with the pelvic cartilaginous symphysis-a noncapsulated cartilage with a naturally high endogenous expression of VEGF (vascular endothelial growth factor). The increased blood flow through these peripheral AVMs explained the drop in aortic blood pressure and led to increased cardiac preload, and high stroke volumes, ultimately resulting in high-output heart failure. Development of pelvic AVMs in this region of high VEGF expression occurred because loss of ENG in endothelial cells leads to increased sensitivity to VEGF and a hyperproliferative response. Development of AVMs and associated progression to high-output heart failure in the absence of endothelial ENG was attenuated by targeting VEGF signaling with an anti-VEGFR2 (VEGF receptor 2) antibody. CONCLUSIONS: ENG promotes the normal balance of VEGF signaling in quiescent endothelial cells to maintain vessel caliber-an essential function in conditions of increased VEGF expression such as local hypoxia or inflammation. In the absence of endothelial ENG, increased sensitivity to VEGF drives abnormal endothelial proliferation in local regions of high VEGF expression, leading to AVM formation and a rapid injurious impact on heart function.


Assuntos
Malformações Arteriovenosas/metabolismo , Endoglina/genética , Endotélio Vascular/metabolismo , Insuficiência Cardíaca/etiologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Malformações Arteriovenosas/complicações , Malformações Arteriovenosas/genética , Malformações Arteriovenosas/patologia , Pressão Sanguínea , Proliferação de Células , Endoglina/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/fisiologia , Endotélio Vascular/patologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
9.
J Surg Case Rep ; 2018(2): rjy023, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29492252

RESUMO

Primary hyperparathyroidism (PHPT) can cause hypercalcaemia secondary to a pathologically high secretion of parathyroid hormone. Rarely this can first manifest as acute psychosis. It is imperative to exclude organic causes of psychosis before labelling the psychosis as primarily psychological. If hypercalcaemia is revealed, investigation is required to elucidate the underlying cause whilst instigating treatment to lower serum calcium levels. If PHPT is the underlying pathology, subsequent treatment involves surgical exploration and resection of the parathyroid adenoma or hyperplasia.

10.
Stem Cell Reports ; 8(5): 1287-1298, 2017 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-28494939

RESUMO

Clinical trials of stem cell therapy to treat ischemic heart disease primarily use heterogeneous stem cell populations. Small benefits occur via paracrine mechanisms that include stimulating angiogenesis, and increased understanding of these mechanisms would help to improve patient outcomes. Cardiosphere-derived-cells (CDCs) are an example of these heterogeneous stem cell populations, cultured from cardiac tissue. CDCs express endoglin, a co-receptor that binds specific transforming growth factor ß (TGFß) family ligands, including bone morphogenetic protein 9 (BMP9). In endothelial cells endoglin regulates angiogenic responses, and we therefore hypothesized that endoglin is required to promote the paracrine pro-angiogenic properties of CDCs. Cre/LoxP technology was used to genetically manipulate endoglin expression in CDCs, and we found that the pro-angiogenic properties of the CDC secretome are endoglin dependent both in vitro and in vivo. Importantly, BMP9 pre-treatment of endoglin-depleted CDCs restores their pro-angiogenic paracrine properties. As BMP9 signaling is normally required to maintain endoglin expression, we propose that media containing BMP9 could be critical for therapeutic CDC preparation.


Assuntos
Endoglina/metabolismo , Miocárdio/citologia , Neovascularização Fisiológica , Comunicação Parácrina , Células-Tronco/fisiologia , Animais , Células Cultivadas , Endoglina/genética , Fator 2 de Diferenciação de Crescimento/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/fisiologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco/metabolismo
11.
Clin Med (Lond) ; 17(2): 183-185, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28365635

RESUMO

A Caucasian female previously diagnosed with anorexia nervosa was referred by psychiatric services to the general medical team. She presented with dehydration, vomiting, weakness, a body mass index of 13 kg/m2 and was treated with intravenous and enteral supplementation. During admission her vomiting worsened and she developed visual hallucinations and confabulation. Neurological examination demonstrated cerebellar signs and bilateral papilloedema on fundoscopy. Subsequent magnetic resonance imaging of the brain revealed a large fourth ventricular tumour causing obstructive hydrocephalus. The tumour was excised and histologically confirmed to be a choroid plexus papilloma. Postoperatively her neurological symptoms and negative feelings towards eating resolved.


Assuntos
Anorexia Nervosa/etiologia , Neoplasias Encefálicas , Papiloma do Plexo Corióideo , Adulto , Feminino , Humanos
12.
Cardiovasc Res ; 99(3): 452-60, 2013 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-23723064

RESUMO

AIMS: Anomalies of the arterial valves, principally bicuspid aortic valve (BAV), are the most common congenital anomalies. The cellular mechanisms that underlie arterial valve development are poorly understood. While it is known that the valve leaflets derive from the outflow cushions, which are populated by cells derived from the endothelium and neural crest cells (NCCs), the mechanism by which these cushions are sculpted to form the leaflets of the arterial valves remains unresolved. We set out to investigate how NCCs participate in arterial valve formation, reasoning that disrupting NCC within the developing outflow cushions would result in arterial valve anomalies, in the process elucidating the normal mechanism of arterial valve leaflet formation. METHODS AND RESULTS: By disrupting Rho kinase signalling specifically in NCC using transgenic mice and primary cultures, we show that NCC condensation within the cardiac jelly is required for correct positioning of the outflow cushions. Moreover, we show that this process is essential for normal patterning of the arterial valve leaflets with disruption leading to a spectrum of valve leaflet patterning anomalies, abnormal positioning of the orifices of the coronary arteries, and abnormalities of the arterial wall. CONCLUSION: NCCs are required at earlier stages of arterial valve development than previously recognized, playing essential roles in positioning the cushions, and patterning the valve leaflets. Abnormalities in the process of NCC condensation at early stages of outflow cushion formation may provide a common mechanism underlying BAV, and also explain the link with arterial wall anomalies and outflow malalignment defects.


Assuntos
Valva Aórtica/embriologia , Coxins Endocárdicos/citologia , Crista Neural/citologia , Animais , Valva Aórtica/anormalidades , Valva Aórtica/citologia , Valva Aórtica/metabolismo , Doença da Válvula Aórtica Bicúspide , Padronização Corporal , Adesão Celular , Comunicação Celular , Células Cultivadas , Anomalias dos Vasos Coronários/embriologia , Anomalias dos Vasos Coronários/metabolismo , Vasos Coronários/embriologia , Vasos Coronários/metabolismo , Modelos Animais de Doenças , Comunicação Atrioventricular/embriologia , Comunicação Atrioventricular/metabolismo , Coxins Endocárdicos/embriologia , Coxins Endocárdicos/metabolismo , Doenças das Valvas Cardíacas/embriologia , Doenças das Valvas Cardíacas/etiologia , Doenças das Valvas Cardíacas/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , Modelos Cardiovasculares , Crista Neural/anormalidades , Crista Neural/metabolismo , Transdução de Sinais , Quinases Associadas a rho/deficiência , Quinases Associadas a rho/genética , Quinases Associadas a rho/metabolismo
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