Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 25.324
Filtrar
1.
Rev Med Suisse ; 16(712): 2031-2036, 2020 Oct 28.
Artigo em Francês | MEDLINE | ID: mdl-33112515

RESUMO

Preeclampsia is a disease which originates in the placenta and is specific to human pregnancy. It is one of the main causes of maternal and perinatal morbidity and mortality. The introduction of assays for angiogenic and anti-angiogenic markers reflecting placental dysfunction, which lies at the root of preeclampsia, is a turning point in the management of women with suspected preeclampsia or with an atypical form of the disease. The sFlt1/PlGF ratio assay, which has been covered by health insurance since July 2019, is a valuable diagnostic aid : the disease can be ruled out, with a high negative predictive value, when the ratio is low, thus avoiding unnecessary hospital admission and premature delivery. A high ratio can help to confirm the diagnosis of preeclampsia, albeit with a lower positive predictive value.


Assuntos
Neovascularização Fisiológica , Pré-Eclâmpsia/diagnóstico , Biomarcadores/análise , Biomarcadores/metabolismo , Feminino , Humanos , Placenta/metabolismo , Placenta/fisiopatologia , Fator de Crescimento Placentário/análise , Fator de Crescimento Placentário/metabolismo , Pré-Eclâmpsia/metabolismo , Gravidez , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/análise , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo
2.
PLoS One ; 15(10): e0240647, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33112891

RESUMO

The World Health Organization declared the COVID-19 epidemic a public health emergency of international concern on March 11th, 2020, and the pandemic is rapidly spreading worldwide. COVID-19 is caused by a novel coronavirus SARS-CoV-2, which enters human target cells via angiotensin converting enzyme 2 (ACE2). We used a number of bioinformatics tools to computationally characterize ACE2 by determining its cell-specific expression in trachea, lung, and small intestine, derive its putative functions, and predict transcriptional regulation. The small intestine expressed higher levels of ACE2 mRNA than any other organ. By immunohistochemistry, duodenum, kidney and testis showed strong signals, whereas the signal was weak in the respiratory tract. Single cell RNA-Seq data from trachea indicated positive signals along the respiratory tract in key protective cell types including club, goblet, proliferating, and ciliary epithelial cells; while in lung the ratio of ACE2-expressing cells was low in all cell types (<2.6%), but was highest in vascular endothelial and goblet cells. Gene ontology analysis suggested that, besides its classical role in the renin-angiotensin system, ACE2 may be functionally associated with angiogenesis/blood vessel morphogenesis. Using a novel tool for the prediction of transcription factor binding sites we identified several putative binding sites within two tissue-specific promoters of the ACE2 gene as well as a new putative short form of ACE2. These include several interferon-stimulated response elements sites for STAT1, IRF8, and IRF9. Our results also confirmed that age and gender play no significant role in the regulation of ACE2 mRNA expression in the lung.


Assuntos
Betacoronavirus/fisiologia , Biologia Computacional , Infecções por Coronavirus/virologia , Pandemias , Peptidil Dipeptidase A/fisiologia , Pneumonia Viral/virologia , Receptores Virais/fisiologia , Envelhecimento/metabolismo , Sítios de Ligação , Proteínas de Transporte/biossíntese , Proteínas de Transporte/genética , Feminino , Regulação Enzimológica da Expressão Gênica , Ontologia Genética , Humanos , Interferons/fisiologia , Pulmão/metabolismo , Masculino , Metaloproteases/biossíntese , Metaloproteases/genética , Neovascularização Fisiológica/fisiologia , Especificidade de Órgãos , Peptidil Dipeptidase A/biossíntese , Peptidil Dipeptidase A/genética , Regiões Promotoras Genéticas , RNA Mensageiro/biossíntese , Receptores Virais/biossíntese , Receptores Virais/genética , Sistema Renina-Angiotensina/fisiologia , Caracteres Sexuais , Análise de Célula Única , Fatores de Transcrição/metabolismo , Sítio de Iniciação de Transcrição , Ligação Viral
3.
Cardiovasc Ther ; 2020: 4018478, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33042222

RESUMO

Background: Endothelial progenitor cells (EPCs) are recruited to injured endothelium and contribute to its regeneration. There is evidence that moderate ethanol consumption prevents the development and progression of atherosclerosis in a variety of in vitro and in vivo models and increases the mobilization of progenitor cells. Furthermore, there are studies that identified ethanol at low concentration as a therapeutic tool to mobilize progenitor cells in peripheral blood. At the same time, the cell number of EPCs represents a close link to cardiovascular system constitution and function and contributes to cardiovascular risk. The aim of this study was to evaluate the effect of low dose ethanol on typical features of endothelial colony-forming cells (ECFCs), a proliferative subtype of EPCs. Methods and Results: We tested whether ethanol impacts the functional abilities of ECFC (e.g., migration, tube formation, and proliferation) using in vitro assays, the intercommunication of ECFC by exploring cell surface molecules by flow cytometry, and the expression of (anti-)angiogenic molecules by ELISA. Low concentrations of ethanol concentration promoted migration, proliferation, and tubule formation of ECFC. The expression of the cell surface marker VE-cadherin, a protein which plays an important role in cell-cell interaction, was enhanced by ethanol, while (anti-)angiogenic molecule expression was not impacted. Conclusion: Ethanol at moderate concentrations increases the angiogenic abilities of endothelial progenitor cells thus possibly contributing to vasoprotection.


Assuntos
Indutores da Angiogênese/farmacologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Progenitoras Endoteliais/efeitos dos fármacos , Etanol/farmacologia , Neovascularização Fisiológica/efeitos dos fármacos , Antígenos CD/metabolismo , Caderinas/metabolismo , Células Cultivadas , Relação Dose-Resposta a Droga , Células Progenitoras Endoteliais/metabolismo , Humanos
4.
Zhonghua Shao Shang Za Zhi ; 36(9): 883-886, 2020 Sep 20.
Artigo em Chinês | MEDLINE | ID: mdl-32972078

RESUMO

Angiogenesis is the core step of wound repair, and vascular endothelial progenitor cells (EPC) play an extremely important role during wound repair. Recent studies have shown that vascular EPC-derived exosomes (EPC-Exo) can protect vessels, promote the proliferation and migration of vascular endothelial cells, and have anti-inflammatory, anti-oxidant and anti-apoptotic effects on vascular endothelial cells. This article reviews the mechanism of vascular EPC-Exo in angiogenesis and its potential applications in wound repair in recent years.


Assuntos
Células Progenitoras Endoteliais , Exossomos , Movimento Celular , Proliferação de Células , Humanos , Neovascularização Fisiológica , Cicatrização
5.
PLoS One ; 15(9): e0237810, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32936824

RESUMO

Cardiovascular diseases are a leading cause of death worldwide. After an ischemic injury, the myocardium undergoes severe necrosis and apoptosis, leading to a dramatic degradation of function. Numerous studies have reported that cardiac fibroblasts (CFs) play a critical role in heart function even after injury. However, CFs present heterogeneous characteristics according to their development stage (i.e., fetal or adult), and the molecular mechanisms by which they maintain heart function are not fully understood. The aim of this study is to explore the hypothesis that a specific population of CFs can repair the injured myocardium in heart failure following ischemic infarction, and lead to a significant recovery of cardiac function. Flow cytometry analysis of CFs defined two subpopulations according to their relative expression of vascular cell adhesion molecule 1 (VCAM1). Whole-transcriptome analysis described distinct profiles for these groups, with a correlation between VCAM1 expression and lymphangiogenesis-related genes up-regulation. Vascular formation assays showed a significant stimulation of lymphatic cells network complexity by VCFs. Injection of human VCAM1-expressing CFs (VCFs) in postinfarct heart failure rat models (ligation of the left anterior descending artery) led to a significant restoration of the left ventricle contraction. Over the course of the experiment, left ventricular ejection fraction and fractional shortening increased by 16.65% ± 5.64% and 10.43% ± 6.02%, respectively, in VCF-treated rats. Histological examinations revealed that VCFs efficiently mobilized the lymphatic endothelial cells into the infarcted area. In conclusion, human CFs present heterogeneous expression of VCAM1 and lymphangiogenesis-promoting factors. VCFs restore the mechanical properties of ventricular walls by mobilizing lymphatic endothelial cells into the infarct when injected into a rat heart failure model. These results suggest a role of this specific population of CFs in the homeostasis of the lymphatic system in cardiac regeneration, providing new information for the study and therapy of cardiac diseases.


Assuntos
Fibroblastos/patologia , Insuficiência Cardíaca/fisiopatologia , Linfangiogênese , Infarto do Miocárdio/fisiopatologia , Miocárdio/patologia , Molécula 1 de Adesão de Célula Vascular/metabolismo , Animais , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Insuficiência Cardíaca/sangue , Humanos , Vasos Linfáticos/metabolismo , Masculino , Infarto do Miocárdio/sangue , Infarto do Miocárdio/patologia , Neovascularização Fisiológica , Ratos , Molécula 1 de Adesão de Célula Vascular/sangue
6.
PLoS One ; 15(9): e0236964, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32931498

RESUMO

BACKGROUND: Short bowel syndrome (SBS) results from significant loss of small intestinal length. In response to this loss, adaptation occurs, with Epidermal Growth Factor Receptor (EGFR) being a key driver. Besides enhanced enterocyte proliferation, we have revealed that adaptation is associated with angiogenesis. Further, we have found that small bowel resection (SBR) is associated with diminished oxygen delivery and elevated levels of hypoxia-inducible factor 1-alpha (HIF1α). METHODS: We ablated EGFR in the epithelium and endothelium as well as HIF1α in the epithelium, ostensibly the most hypoxic element. Using these mice, we determined the effects of these genetic manipulations on intestinal blood flow after SBR using photoacoustic microscopy (PAM), intestinal adaptation and angiogenic responses. Then, given that endothelial cells require a stromal support cell for efficient vascularization, we ablated EGFR expression in intestinal subepithelial myofibroblasts (ISEMFs) to determine its effects on angiogenesis in a microfluidic model of human small intestine. RESULTS: Despite immediate increased demand in oxygen extraction fraction measured by PAM in all mouse lines, were no differences in enterocyte and endothelial cell EGFR knockouts or enterocyte HIF1α knockouts by POD3. Submucosal capillary density was also unchanged by POD7 in all mouse lines. Additionally, EGFR silencing in ISEMFs did not impact vascular network development in a microfluidic device of human small intestine. CONCLUSIONS: Overall, despite the importance of EGFR in facilitating intestinal adaptation after SBR, it had no impact on angiogenesis in three cell types-enterocytes, endothelial cells, and ISEMFs. Epithelial ablation of HIF1α also had no impact on angiogenesis in the setting of SBS.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Intestino Delgado/irrigação sanguínea , Neovascularização Fisiológica , Síndrome do Intestino Curto/cirurgia , Animais , Receptores ErbB/genética , Receptores ErbB/fisiologia , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Intestino Delgado/metabolismo , Masculino , Camundongos , Técnicas Analíticas Microfluídicas , Miofibroblastos , Síndrome do Intestino Curto/metabolismo
7.
PLoS One ; 15(9): e0238879, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32915887

RESUMO

BACKGROUND: Mesenchymal stem cell-derived extracellular vesicles (EVs) appear to be a very exciting treatment option for heart disease. Here, we used a swine model of chronic myocardial ischemia to evaluate the efficacy of a less-invasive method of injection of EVs via a peripheral intravenous route. METHODS: Sixteen Yorkshire swine underwent placement of an ameroid constrictor on the left circumflex (LCx) artery at age 11 weeks to induce chronic myocardial ischemia. Two weeks later, they were divided into two groups: control (CON; n = 8), and intravenous injection of EVs (EVIV; n = 8). At 18 weeks of age, animals underwent final analysis and euthanasia. The chronically ischemic myocardium (LCx territory) was harvested for analysis. RESULTS: Intravenous injection (IV) of EVs induced several pro-angiogenic markers such as MAPK, JNK but not Akt. Whereas IV injections of EVs decreased VEGFR2 expression and inhibited apoptotic signaling (caspase 3), they increased expression of VEGFR1 that is believed to be anti-angiogenic. Injection of EVs did not result in an increase in vessel density and blood flow when compared to the control group. CONCLUSIONS: Although IV injection of EVs upregulated several pro-angiogenic signaling pathways, it failed to induce changes in vascular density in the chronically ischemic myocardium. Thus, a lack of increase in vascular density at the doses tested failed to elicit a functional response in ischemic myocardium.


Assuntos
Modelos Animais de Doenças , Vesículas Extracelulares/transplante , Células-Tronco Mesenquimais/citologia , Isquemia Miocárdica/terapia , Neovascularização Fisiológica , Animais , Apoptose , Doença Crônica , Circulação Coronária , Hemodinâmica , Humanos , Masculino , Suínos
8.
Int J Nanomedicine ; 15: 6409-6420, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32922008

RESUMO

Aim: Tumor cell-derived microparticles (MP) can function as a targeted delivery carrier for anti-tumor drugs. Here, we aimed to generate paclitaxel-loaded microparticles (MP-PTX) from HeLa cells and examined its therapeutic potential on human cervical carcinoma. Methods: MP-PTX was generated from HeLa cells by ultraviolet radiation and subsequent centrifugation. The particle size, drug loading rate, and stability of MP-PTX were examined in vitro. Flow cytometry and the MTT assay were performed to test the inhibitory effect of MP-PTX using different cell lines. Immunodeficient mice bearing HeLa cervical carcinoma were treated with 0.9% normal saline, MP, paclitaxel (PTX) (2.5 mg/kg), or MP-PTX (PTX content identical to PTX group) every day for 6 consecutive days. Tumor volume and animal survival were observed. Micro 18F-FDG PET/CT was performed to monitor the therapeutic efficacy. The proliferation activity of cells and microvessel density in tumor tissues were determined by immunohistochemical staining using Ki-67 and CD31, respectively. Results: Dynamic laser scattering measurements showed that the particle size of MP-PTX was 285.58 ± 2.95 nm and the polydispersity index was 0.104 ± 0.106. And the particle size of MP-PTX was not change at 4°C for at least one week. More than 1% of PTX in the medium could be successfully encapsulated into HeLa cell-derived MP. When compared with PTX, MP-PTX treatment significantly increased apoptosis of tumor cells and reduced their proliferation. In addition, MP-PTX showed lower toxicity to normal human umbilical vein endothelial cells (HUVEC) than PTX. In vivo studies further demonstrated that MP-PTX treatment significantly inhibited the growth of cervical carcinoma, prolonged the survival of tumor-bearing mice, and reduced the toxicity of PTX. Immunohistochemical staining revealed that MP-PTX treatment led to decreased Ki-67 positive tumor cells and decreased microvessel density in tumor tissues. Conclusion: Our results demonstrated that HeLa-derived MP-PTX significantly enhanced the anti-cancer effects of PTX with reduced toxicity, which may provide a novel strategy for the treatment of cervical carcinoma.


Assuntos
Micropartículas Derivadas de Células/metabolismo , Paclitaxel/uso terapêutico , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Micropartículas Derivadas de Células/efeitos dos fármacos , Portadores de Fármacos/química , Células Endoteliais/efeitos dos fármacos , Feminino , Células HeLa , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Neovascularização Fisiológica/efeitos dos fármacos , Paclitaxel/farmacologia , Tamanho da Partícula
9.
J Vis Exp ; (162)2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32831307

RESUMO

Pathological choroidal angiogenesis, a salient feature of age-related macular degeneration, leads to vision impairment and blindness. Endothelial cell (EC) proliferation assays using human retinal microvascular endothelial cells (HRMECs) or isolated primary retinal ECs are widely used in vitro models to study retinal angiogenesis. However, isolating pure murine retinal endothelial cells is technically challenging and retinal ECs may have different proliferation responses than choroidal endothelial cells and different cell/cell interactions. A highly reproducible ex vivo choroidal sprouting assay as a model of choroidal microvascular proliferation was developed. This model includes the interaction between choroid vasculature (EC, macrophages, pericytes) and retinal pigment epithelium (RPE). Mouse RPE/choroid/scleral explants are isolated and incubated in growth-factor-reduced basal membrane extract (BME) (day 0). Medium is changed every other day and choroid sprouting is quantified at day 6. The images of individual choroid explant are taken with an inverted phase microscope and the sprouting area is quantified using a semi-automated macro plug-in to the ImageJ software developed in this lab. This reproducible ex vivo choroidal sprouting assay can be used to assess compounds for potential treatment and for microvascular disease research to assess pathways involved in choroidal micro vessel proliferation using wild type and genetically modified mouse tissue.


Assuntos
Bioensaio/métodos , Corioide/irrigação sanguínea , Microvasos/crescimento & desenvolvimento , Neovascularização Fisiológica , Animais , Neovascularização de Coroide/metabolismo , Neovascularização de Coroide/patologia , Células Endoteliais/metabolismo , Humanos , Camundongos Endogâmicos C57BL , Receptores Acoplados a Proteínas-G/metabolismo
10.
Life Sci ; 259: 118246, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32791151

RESUMO

BACKGROUND: Diabetic foot ulcer (DFU), one of the diabetic complications, brings high burden to diabetic patients. Hyperbaric oxygen therapy (HBOT) has been proven to be an effective clinical method for the treatment of DFU. However, the mechanisms still to be elucidated. METHODS: Diabetic foot mice model was established, and treated with hyperbaric oxygen. Haematoxylin & eosin (H&E) staining and Masson's trichrome staining were used for the analysis of wound healing. Human skin fibroblast (HSF) and human umbilical vein endothelial cell (HUVECS) were exposed to high glucose and hyperbaric oxygen for studying the mechanism of hyperbaric oxygen promoted wound healing in vitro. Wound healing assay, reactive oxygen species (ROS) assay, cell proliferation assay and tube formation assay were used for the analysis of wound healing. Quantitative-polymerase chain reaction (Q-PCR), Western blotting and enzyme-linked immunosorbent assay (ELISA) were used for the analysis of gene expression. RESULTS: HBOT facilitated wound healing in DFU mice model, and promoted the expression of HIF-1α, NF-κB, VEGFA, SDF-1, VEGFR2 and CXCR4. Hyperbaric oxygen promoted the proliferation, migration and ROS production, as well as the expression of SDF-1 and VEGFA in HSF. HBOT stimulated the proliferation, migration and tube formation, as well as the expression of CXCR4 and VEGFR2 in HUVECS. CONCLUSION: Hyperbaric oxygen potentiates angiogenesis and diabetic wound healing by activating HIF-1α signaling, so as to promote the expression of VEGF/SDF-1 in HSF and the expression of VEGFR/CXCR4 in HUVECS, ultimately to promote the proliferation of HSF and the angiogenesis of HUVECS.


Assuntos
Diabetes Mellitus Experimental/terapia , Pé Diabético/terapia , Cicatrização/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Diabetes Mellitus Experimental/fisiopatologia , Pé Diabético/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Feminino , Fibroblastos/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Oxigenação Hiperbárica/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Neovascularização Patológica/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Neovascularização Fisiológica/fisiologia , Transdução de Sinais , Pele/metabolismo , Estreptozocina/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
11.
Nat Commun ; 11(1): 4102, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32796823

RESUMO

Emerging evidence suggests that intestinal stromal cells (IntSCs) play essential roles in maintaining intestinal homeostasis. However, the extent of heterogeneity within the villi stromal compartment and how IntSCs regulate the structure and function of specialized intestinal lymphatic capillary called lacteal remain elusive. Here we show that selective hyperactivation or depletion of YAP/TAZ in PDGFRß+ IntSCs leads to lacteal sprouting or regression with junctional disintegration and impaired dietary fat uptake. Indeed, mechanical or osmotic stress regulates IntSC secretion of VEGF-C mediated by YAP/TAZ. Single-cell RNA sequencing delineated novel subtypes of villi fibroblasts that upregulate Vegfc upon YAP/TAZ activation. These populations of fibroblasts were distributed in proximity to lacteal, suggesting that they constitute a peri-lacteal microenvironment. Our findings demonstrate the heterogeneity of IntSCs and reveal that distinct subsets of villi fibroblasts regulate lacteal integrity through YAP/TAZ-induced VEGF-C secretion, providing new insights into the dynamic regulatory mechanisms behind lymphangiogenesis and lymphatic remodeling.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Ciclo Celular/metabolismo , Fibroblastos/metabolismo , Mucosa Intestinal/metabolismo , Fatores de Transcrição/metabolismo , Fator C de Crescimento do Endotélio Vascular/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Proteínas de Ciclo Celular/genética , Células Cultivadas , Análise por Conglomerados , Ensaio de Imunoadsorção Enzimática , Fibroblastos/ultraestrutura , Citometria de Fluxo , Imunofluorescência , Hibridização in Situ Fluorescente , Mucosa Intestinal/ultraestrutura , Linfangiogênese/genética , Linfangiogênese/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica , Neovascularização Fisiológica/genética , Neovascularização Fisiológica/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/genética , Fator C de Crescimento do Endotélio Vascular/genética
12.
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
13.
Vascul Pharmacol ; 133-134: 106778, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32784009

RESUMO

Angiogenesis has critical roles in numerous physiologic processes during embryonic and adult life such as wound healing and tissue regeneration. However, aberrant angiogenic processes have also been involved in the pathogenesis of several disorders such as cancer and diabetes mellitus. Vascular endothelial growth factor (VEGF) is implicated in the regulation of this process in several physiologic and pathologic conditions. Notably, several non-coding RNAs (ncRNAs) have been shown to influence angiogenesis through modulation of expression of VEGF or other angiogenic factors. In the current review, we summarize the function and characteristics of microRNAs and long non-coding RNAs which regulate angiogenic processes. Understanding the role of these transcripts in the angiogenesis can facilitate design of therapeutic strategies to defeat the pathogenic events during this process especially in the human malignancies. Besides, angiogenesis-related mechanisms can improve tissue regeneration after conditions such as arteriosclerosis, myocardial infarction and limb ischemia. Thus, ncRNA-regulated angiogenesis can be involved in the pathogenesis of several disorders.


Assuntos
Células Endoteliais/metabolismo , MicroRNAs/metabolismo , Neoplasias/irrigação sanguínea , Neoplasias/metabolismo , Neovascularização Patológica , Neovascularização Fisiológica , RNA Longo não Codificante/metabolismo , Animais , Células Endoteliais/patologia , Regulação da Expressão Gênica , Humanos , MicroRNAs/genética , Neoplasias/genética , Neoplasias/patologia , Neovascularização Patológica/genética , Neovascularização Fisiológica/genética , RNA Longo não Codificante/genética , Transdução de Sinais , Microambiente Tumoral
14.
Life Sci ; 258: 118195, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32781073

RESUMO

AIMS: The estrogen-ERα axis participates in osteoblast maturation. This study was designed to further evaluated the roles of the estrogen-ERα axis in bone healing and the possible mechanisms. MAIN METHODS: Female ICR mice were created a metaphyseal bone defect in the left femurs and administered with methylpiperidinopyrazole (MPP), an inhibitor of ERα. Bone healing was evaluated using micro-computed tomography. Colocalization of ERα with alkaline phosphatase (ALP) and ERα translocation to mitochondria were determined. Levels of ERα, ERß, PECAM-1, VEGF, and ß-actin were immunodetected. Expression of chromosomal Runx2, ALP, and osteocalcin mRNAs and mitochondrial cytochrome c oxidase (COX) I and COXII mRNAs were quantified. Angiogenesis was measured with immunohistochemistry. KEY FINDINGS: Following surgery, the bone mass was time-dependently augmented in the bone-defect area. Simultaneously, levels of ERα were specifically upregulated and positively correlated with bone healing. Administration of MPP to mice consistently decreased levels of ERα and bone healing. As to the mechanisms, osteogenesis was enhanced in bone healing, but MPP attenuated osteoblast maturation. In parallel, expressions of osteogenesis-related ALP, Runx2, and osteocalcin mRNAs were induced in the injured zone. Treatment with MPP led to significant inhibition of the alp, runx2, and osteocalcin gene expressions. Remarkably, administration of MPP lessened translocation of ERα to mitochondria and expressions of mitochondrial energy production-related coxI and coxII genes. Furthermore, exposure to MPP decreased levels of PECAM-1 and VEGF in the bone-defect area. SIGNIFICANCE: The present study showed the contributions of the estrogen-ERα axis to bone healing through stimulation of energy production, osteoblast maturation, and angiogenesis.


Assuntos
Regeneração Óssea , Diferenciação Celular , Metabolismo Energético , Receptor alfa de Estrogênio/metabolismo , Neovascularização Fisiológica , Osteoblastos/citologia , Transdução de Sinais , Fosfatase Alcalina/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Regeneração Óssea/efeitos dos fármacos , Calo Ósseo/efeitos dos fármacos , Calo Ósseo/patologia , Diferenciação Celular/efeitos dos fármacos , Cromossomos de Mamíferos/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/genética , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Metabolismo Energético/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Camundongos Endogâmicos ICR , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Tamanho do Órgão/efeitos dos fármacos , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteocalcina/metabolismo , Osteogênese/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Pirazóis/administração & dosagem , Pirazóis/farmacologia , Regulação para Cima/efeitos dos fármacos , Cicatrização/efeitos dos fármacos
15.
Arterioscler Thromb Vasc Biol ; 40(9): 2293-2309, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32757648

RESUMO

OBJECTIVE: Extracellular vesicles (EVs) have the potential to act as intercellular communicators. The aims were to characterize circulating EVs in patients with pulmonary arterial hypertension (PAH) and to explore whether these EVs contribute to endothelial activation and angiogenesis. Approach and Results: Patients with PAH (n=70) and healthy controls (HC; n=20) were included in this cross-sectional study. EVs were characterized and human pulmonary endothelial cells (hPAECs) were incubated with purified EVs. Endothelial cell activity and proangiogenic markers were analyzed. Tube formation analysis was performed for hPAECs, and the involvement of PSGL-1 (P-selectin glycoprotein ligand 1) was evaluated. The numbers of CD62P+, CD144+, and CD235a EVs were higher in blood from PAH compared with HC. Thirteen proteins were differently expressed in PAH and HC EVs, where complement fragment C1q was the most significantly elevated protein (P=0.0009) in PAH EVs. Upon EVs-internalization in hPAECs, more PAH compared with HC EVs evaded lysosomes (P<0.01). As oppose to HC, PAH EVs stimulated hPAEC activation and induced transcription and translation of VEGF-A (vascular endothelial growth factor A; P<0.05) and FGF (fibroblast growth factor; P<0.005) which were released in the cell supernatant. These proangiogenic proteins were higher in patient with PAH plasma compered with HC. PAH EVs induced a complex network of angiotubes in vitro, which was abolished by inhibitory PSGL-1antibody. Anti-PSGL-1 also inhibited EV-induced endothelial cell activation and PAH EV dependent increase of VEGF-A. CONCLUSIONS: Patients with PAH have higher levels of EVs harboring increased amounts of angiogenic proteins, which induce activation of hPAECs and in vitro angiogenesis. These effects were partly because of platelet-derived EVs evasion of lysosomes upon internalization within hPAEC and through possible involvement of P-selectin-PSGL-1 pathway.


Assuntos
Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Vesículas Extracelulares/metabolismo , Neovascularização Fisiológica , Hipertensão Arterial Pulmonar/metabolismo , Artéria Pulmonar/metabolismo , Idoso , Estudos de Casos e Controles , Células Cultivadas , Estudos Transversais , Células Endoteliais/ultraestrutura , Endotélio Vascular/fisiopatologia , Endotélio Vascular/ultraestrutura , Vesículas Extracelulares/ultraestrutura , Feminino , Fator 2 de Crescimento de Fibroblastos/metabolismo , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Selectina-P/metabolismo , Hipertensão Arterial Pulmonar/patologia , Hipertensão Arterial Pulmonar/fisiopatologia , Artéria Pulmonar/fisiopatologia , Artéria Pulmonar/ultraestrutura , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo
16.
Stroke ; 51(9): 2844-2853, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32772683

RESUMO

BACKGROUND AND PURPOSE: Although VEGF165 (vascular endothelial growth factor-165) is able to enhance both angiogenesis and neurogenesis, it also increases vascular permeability through the blood-brain barrier. Heparan sulfate (HS) sugars play important roles in regulating VEGF bioactivity in the pericellular compartment. Here we asked whether an affinity-purified VEGF165-binding HS (HS7) could augment endogenous VEGF activity during stroke recovery without affecting blood-brain barrier function. METHODS: Both rat brain endothelial cell line 4 and primary rat neural progenitor cells were used to evaluate the potential angiogenic and neurogenic effects of HS7 in vitro. For in vivo experiments, male Sprague-Dawley rats were subjected to 100 minutes of transient focal cerebral ischemia, then treated after 4 days with either PBS or HS7. One week later, infarct volume, behavioral sequelae, immunohistochemical markers of angiogenesis and neural stem cell proliferation were assessed. RESULTS: HS7 significantly enhanced VEGF165-mediated angiogenesis in rat brain endothelial cell line 4 brain endothelial cells, and increased the proliferation and differentiation of primary neural progenitor cells, both via the VEGFR2 (vascular endothelial growth factor receptor 2) pathway. Intracerebroventricular injection of HS7 improved neurological outcome in ischemic rats without changing infarct volumes. Immunostaining of the compromised cerebrum demonstrated increases in collagen IV/Ki67 and nestin/Ki67 after HS7 exposure, consistent with its ability to promote angiogenesis and neurogenesis, without compromising blood-brain barrier integrity. CONCLUSIONS: A VEGF-activating glycosaminoglycan sugar, by itself, is able to enhance endogenous VEGF165 activity during the post-ischemic recovery phase of stroke.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Heparitina Sulfato/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/uso terapêutico , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Heparitina Sulfato/administração & dosagem , Infarto da Artéria Cerebral Média/prevenção & controle , Injeções Intraventriculares , Ataque Isquêmico Transitório/tratamento farmacológico , Ataque Isquêmico Transitório/fisiopatologia , Masculino , Neovascularização Fisiológica/efeitos dos fármacos , Células-Tronco Neurais/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Fator A de Crescimento do Endotélio Vascular/administração & dosagem , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
17.
Chem Biol Interact ; 329: 109202, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32717189

RESUMO

Triple-negative breast cancer (TNBC) is highly metastatic and lacks effective therapeutic targets among several subtypes of breast cancer. Cancer metastasis promotes the malignancy of TNBC and is closely related to the poor prognosis of the TNBC patients. We aim to explore novel agents that effectively inhibit cancer metastasis to treat TNBC. In our study, 2-Methoxy-5((3,4,5-trimethosyphenyl)seleninyl) phenol (SQ), a CA-4 analogue, could inhibit cell motility and invasion in MDA-MB-231 cells, and the mechanism is closely associated to the inhibition of epithelial-to-mesenchymal transition (EMT). Meanwhile, SQ significantly inhibited the expression and secretion of vascular endothelial growth factor (VEGF) in MDA-MB-231 cells. Moreover, the conditioned medium from SQ-treated MDA-MB-231 cells significantly inhibited the motility and invasion of human umbilical vein endothelial cells (HUVECs), which was correlated with the inhibition of EMT process in HUVECs. In addition, exogenous application of VEGF reversed the occurrence of EMT in HUVECs which stimulated by conditioned medium from SQ-treated cells. Furthermore, SQ inhibited vasculogenic mimicry (VM) formation in MDA-MB-231 cells, which was associated with VE-cadherin and EphA2 down-regulation. This study indicates that SQ inhibits MDA-MB-231 cell metastasis through suppressing EMT and VEGF, thereby implicating this compound might be a potential therapeutic agent against metastatic TNBC.


Assuntos
Transição Epitelial-Mesenquimal/efeitos dos fármacos , Compostos Organosselênicos/farmacologia , Fenóis/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Regulação para Baixo/efeitos dos fármacos , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Metaloproteinase 9 da Matriz/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Compostos Organosselênicos/química , Fenóis/química , Receptor EphA2/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Fator A de Crescimento do Endotélio Vascular/genética
18.
Int J Nanomedicine ; 15: 4311-4324, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606679

RESUMO

Purpose: By providing a stem cell microenvironment with particular bioactive constituents in vivo, synthetic biomaterials have been progressively successful in stem cell-based tissue regeneration by enhancing the engraftment and survival of transplanted cells. Designs with bioactive motifs to influence cell behavior and with D-form amino acids to modulate scaffold stability may be critical for the development and optimization of self-assembling biomimetic hydrogel scaffolds for stem cell therapy. Materials and Methods: In this study, we linked naphthalene (Nap) covalently to a short D-form peptide (Nap-DFDFG) and the C domain of insulin-like growth factor-1 (IGF-1C) as a functional hydrogel-based scaffolds, and we hypothesized that this hydrogel could enhance the therapeutic efficiency of human placenta-derived mesenchymal stem cells (hP-MSCs) in a murine acute kidney injury (AKI) model. Results: The self-assembling peptide was constrained into a classical ß-sheet structure and showed hydrogel properties. Our results revealed that this hydrogel exhibited increased affinity for IGF-1 receptor. Furthermore, cotransplantation of the ß-IGF-1C hydrogel and hP-MSCs contributed to endogenous regeneration post-injury and boosted angiogenesis in a murine AKI model, leading to recovery of renal function. Conclusion: This hydrogel could provide a favorable niche for hP-MSCs and thereby rescue renal function in an AKI model by promoting cell survival and angiogenesis. In conclusion, by covalently linking the desired functional groups to D-form peptides to create functional hydrogels, self-assembling ß-sheet peptide hydrogels may serve as a promising platform for tissue-engineering and stem cell therapy.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Hidrogéis/química , Fator de Crescimento Insulin-Like I/química , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Peptídeos/química , Lesão Renal Aguda/fisiopatologia , Animais , Materiais Biocompatíveis/química , Sobrevivência Celular , Feminino , Fibrose , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Hidrogéis/síntese química , Rim/patologia , Rim/fisiopatologia , Camundongos Transgênicos , Neovascularização Fisiológica , Placenta/citologia , Gravidez , Conformação Proteica em Folha beta , Domínios Proteicos
19.
Nat Commun ; 11(1): 3653, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32694534

RESUMO

The vasculature represents a highly plastic compartment, capable of switching from a quiescent to an active proliferative state during angiogenesis. Metabolic reprogramming in endothelial cells (ECs) thereby is crucial to cover the increasing cellular energy demand under growth conditions. Here we assess the impact of mitochondrial bioenergetics on neovascularisation, by deleting cox10 gene encoding an assembly factor of cytochrome c oxidase (COX) specifically in mouse ECs, providing a model for vasculature-restricted respiratory deficiency. We show that EC-specific cox10 ablation results in deficient vascular development causing embryonic lethality. In adult mice induction of EC-specific cox10 gene deletion produces no overt phenotype. However, the angiogenic capacity of COX-deficient ECs is severely compromised under energetically demanding conditions, as revealed by significantly delayed wound-healing and impaired tumour growth. We provide genetic evidence for a requirement of mitochondrial respiration in vascular endothelial cells for neoangiogenesis during development, tissue repair and cancer.


Assuntos
Mitocôndrias/metabolismo , Neoplasias/patologia , Neovascularização Patológica/patologia , Neovascularização Fisiológica , Cicatrização/fisiologia , Trifosfato de Adenosina/metabolismo , Alquil e Aril Transferases/genética , Alquil e Aril Transferases/metabolismo , Animais , Linhagem Celular Tumoral/transplante , Respiração Celular , Modelos Animais de Doenças , Embrião de Mamíferos , Desenvolvimento Embrionário/fisiologia , Células Endoteliais/fisiologia , Endotélio Vascular/citologia , Endotélio Vascular/fisiologia , Feminino , Técnicas de Inativação de Genes , Humanos , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Mitocôndrias/genética , Neoplasias/irrigação sanguínea , Fosforilação Oxidativa
20.
Int Heart J ; 61(4): 815-821, 2020 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-32684588

RESUMO

MiR-134-5p was found to have potential diagnostic value for myocardial infarction (MI), but its biological role in MI has not been reported. In this study, MI mouse model was established. Quantitative real-time PCR (qRT-PCR) and western blot were used to measure the expression of miR-134-5p, lysine demethylase 2A (KDM2A), and vascular endothelial growth factor (VEGF). Dual-Luciferase reporter (DLR) assay was used to explore the relationship between miR-134-5p and KDM2A. The influence of miR-134-5p on cardiomyocytes apoptosis was detected using methyl thiazolyl tetrazolium (MTT) assay. The results revealed that miR-134-5p was highly expressed in infarction tissues of MI mice. Knockdown of miR-134-5p inhibited hypoxia/reoxygenation (H/R) -induced cardiomyocyte apoptosis. In addition, KDM2A was the target gene of miR-134-5p and negatively regulated by miR-134-5p. The promotion effect on the protein level of KDM2A and VEGF induced by miR-134-5p inhibitor can be reversed by shKDM2A in cardiomyocytes. Further, silencing of miR-134-5p promoted myocardial angiogenesis and inhibited myocardial apoptosis via upregulating KDM2A in MI mice. Taken together, our research revealed that knockdown of miR-134-5p increased KDM2A expression, thereby suppressing myocardial apoptosis and promoting myocardial angiogenesis.


Assuntos
Histona Desmetilases com o Domínio Jumonji/metabolismo , MicroRNAs/metabolismo , Infarto do Miocárdio/metabolismo , Animais , Apoptose , Histona Desmetilases com o Domínio Jumonji/genética , Masculino , Camundongos Endogâmicos C57BL , Neovascularização Fisiológica
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA