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1.
DNA Cell Biol ; 39(1): 8-15, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31825254

RESUMEN

Atherosclerosis is a major disease that seriously harms human health and is known as the "number one killer" in developed countries and the leading cause of death worldwide. Glutamine is the most abundant nonessential amino acid in the human blood that has multifaceted effects on the body. Recent studies showed that glutamine is negatively corrected with the progression of atherosclerotic lesions. In this review, we focused on the relationship of glutamine with macrophage polarization, nitrification stress, oxidative stress injury, myocardial ischemia-reperfusion injury, and therapeutic angiogenesis to review its roles in atherosclerotic cardiovascular disease.


Asunto(s)
Aterosclerosis/sangre , Enfermedades Cardiovasculares/sangre , Glutamina/sangre , Activación de Macrófagos , Estrés Oxidativo , Animales , Aterosclerosis/patología , Enfermedades Cardiovasculares/patología , Progresión de la Enfermedad , Humanos , Daño por Reperfusión Miocárdica/sangre , Daño por Reperfusión Miocárdica/fisiopatología , Neovascularización Patológica/sangre , Neovascularización Patológica/fisiopatología
2.
Adv Exp Med Biol ; 1131: 489-504, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31646522

RESUMEN

Store-Operated Ca2+ Entry (SOCE) is an important Ca2+ influx pathway expressed by several excitable and non-excitable cell types. SOCE is recognized as relevant signaling pathway not only for physiological process, but also for its involvement in different pathologies. In fact, independent studies demonstrated the implication of essential protein regulating SOCE, such as STIM, Orai and TRPCs, in different pathogenesis and cell disorders, including cardiovascular disease, muscular dystrophies and angiogenesis. Compelling evidence showed that dysregulation in the function and/or expression of isoforms of STIM, Orai or TRPC play pivotal roles in cardiac hypertrophy and heart failure, vascular remodeling and hypertension, skeletal myopathies, and angiogenesis. In this chapter, we summarized the current knowledge concerning the mechanisms underlying abnormal SOCE and its involvement in some diseases, as well as, we discussed the significance of STIM, Orai and TRPC isoforms as possible therapeutic targets for the treatment of angiogenesis, cardiovascular and skeletal muscle diseases.


Asunto(s)
Calcio , Enfermedades Cardiovasculares , Enfermedades Musculares , Neovascularización Patológica , Calcio/metabolismo , Canales de Calcio , Señalización del Calcio , Enfermedades Cardiovasculares/fisiopatología , Humanos , Transporte Iónico , Enfermedades Musculares/fisiopatología , Neovascularización Patológica/fisiopatología
3.
Presse Med ; 48(9): 919-930, 2019 Sep.
Artículo en Francés | MEDLINE | ID: mdl-31543394

RESUMEN

Giant cell arteritis (GCA) is a large-vessel vasculitis involving the aorta and its main branches, especially supra aortic branches. Although much progress has been made, the pathophysiology remains incompletely understood. An initial trigger, suspected of infectious origin, lead to the maturation and recruitment of dendritic cells (DC). The lack of migration of these DC allows the local recruitment of T-lymphocytes (LT). These LT- CD4+ polarize in Type 1 helper (Th1), Th17 but also Th9. A qualitative and quantitative deficit in regulatory T cells (Treg) is observed under the influence of IL-21 overproduction. In addition, an imbalance in the Th17/Treg balance is favored by IL-6. The secretion of IFN-γ, IL-17, IL-6, IL-33 is responsible for a sustained local inflammatory reaction that is organized around tertiary lymphoid follicles. Locally recruited macrophages secrete reactive forms of oxygen together with VEGF and PDGF. These growth factors, together with neurotrophins and endothelin contribute to increase the proliferation of vascular smooth muscle cells (VSMCs). The imbalance between matrix metalloproteases (MMP)-2, MMP-9 and MMP-14 and tissue inhibitors of metalloproteases (TIMP)-1 and TIMP-2 also contribute to the remodeling process occurring in the vessel wall. Finally, arterial neovascularization contribute to the perpetuation of lymphocyte recruitment. This persistent remodeling is sometimes complicated by ischemic events responsible for the initial severity of the disease.


Asunto(s)
Arteritis de Células Gigantes/fisiopatología , Remodelación Vascular/fisiología , Animales , Linfocitos B/fisiología , Linfocitos T CD4-Positivos/fisiología , Movimiento Celular , Proliferación Celular , Células Dendríticas/fisiología , Modelos Animales de Enfermedad , Predisposición Genética a la Enfermedad , Arteritis de Células Gigantes/tratamiento farmacológico , Arteritis de Células Gigantes/etiología , Arteritis de Células Gigantes/patología , Humanos , Interferón gamma/metabolismo , Interleucina-17/metabolismo , Interleucina-33/metabolismo , Interleucina-6/fisiología , Interleucinas/biosíntesis , Activación de Linfocitos/fisiología , Macrófagos/metabolismo , Metaloproteinasas de la Matriz/metabolismo , Músculo Liso Vascular/patología , Neovascularización Patológica/fisiopatología , Linfocitos T Reguladores/fisiología , Células Th17/fisiología
4.
Semin Thromb Hemost ; 45(6): 622-628, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31398734

RESUMEN

Data regarding the effect of coagulation proteins on enhancing angiogenesis and tumor growth are ample. Thus, inhibition of the coagulation system in an attempt to reduce tumor growth and metastasis seems appealing. However, such molecules as direct oral anticoagulants, warfarin and heparins, may impose a bleeding tendency, limiting the treatment dose that can be used. The heparanase protein, as a cofactor for tissue factor (TF) activity, enhances activation of the coagulation system and in addition has several nonhemostatic effects increasing tumor growth. The molecules currently investigated in the field of cancer and coagulation are heparin mimetics and inhibitors of heparanase derived from TF pathway inhibitor 2. Both groups of molecules are inhibitors of heparanase and in addition pose a low bleeding tendency. Hence, interfering in heparanase activity seems to be a promising target for development of antitumor drugs.


Asunto(s)
Anticoagulantes/uso terapéutico , Coagulación Sanguínea/genética , Neoplasias/tratamiento farmacológico , Neovascularización Patológica/fisiopatología , Anticoagulantes/farmacología , Humanos
5.
Anticancer Res ; 39(7): 3641-3649, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31262890

RESUMEN

BACKGROUND/AIM: Amentoflavone has been shown to be effective against a variety of cancer cells, but its role in bladder cancer remains unclear. Thus, the aim of this study is to evaluate whether amentoflavone may induce toxicity effect of bladder cancer. MATERIALS AND METHODS: Herein, we evaluated amentoflavone effects in a human bladder cancer cell line TSGH8301 in vitro. RESULTS: Amentoflavone caused significant cytotoxicity in TSGH8301 cells at a concentration as low as 200 µM. FAS/FASL-dependent extrinsic apoptosis and mitochondria-dependent intrinsic apoptosis were observed in amentoflavone-treated cells in a dose-dependent manner. Levels of several proapoptotic proteins, such as FAS, FAS-ligand and BAX (B-cell lymphoma 2 associated X) were increased following amentoflavone treatment. Meanwhile, anti-apoptotic MCL-1 (myeloid cell leukemia sequence 1) and cellular FLICE-inhibitory protein (C-FLIP) protein levels were reduced. Additionally, angiogenesis and proliferation-related proteins, including matrix metalloproteinase (MMP)-2, -9, vascular endothelial growth factor (VEGF), urokinase-type plasminogen actvator (uPA) and cyclin D1 were diminished by amentoflavone. CONCLUSION: Amentoflavone induced toxicity of bladder cancer by inhibiting tumor progression and inducing apoptosis signaling transduction.


Asunto(s)
Antineoplásicos/farmacología , Biflavonoides/farmacología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proteína Ligando Fas/metabolismo , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Neovascularización Patológica/fisiopatología , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/fisiopatología , Receptor fas/metabolismo
6.
J Agric Food Chem ; 67(32): 8855-8867, 2019 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-31343893

RESUMEN

Abalone (Haliotis discus hannai) is a precious seafood in the market. It has been reported that biological active substances derived from abalone have anti-oxidative, anti-inflammatory, anti-bacterial, and anti-thrombosis potential. However, there were few studies to assess whether they have anti-cancer potential. In this study, we evaluated the anti-metastasis and anti-pro-angiogenic factors and mechanism of action of boiled abalone byproduct peptide (BABP, EMDEAQDPSEW) in human fibrosarcoma (HT1080) cells and human umbilical vein endothelial cells (HUVECs). The results demonstrated that BABP treatment significantly lowers migration and the invasion of HT1080 cells and HUVECs. BABP inhibits phorbol 12-myristate 13-acetate (PMA)-induced matrix metalloproteinase (MMP) expression and activity by blocking mitogen-activated protein kinases (MAPKs) and NF-κB signaling and hypoxia-induced vascular endothelial growth factor (VEGF) secretion and hypoxia inducible factor (HIF)-1α accumulation through suppressing the AKT/mTOR signal pathway. BABP treatment inhibits VEGF-induced VEGFR-2 expression and tube formation in HUVECs. The effect of BABP on anti-metastatic and anti-vascular activity in HT1080 cells and HUVECs revealed that BABP may be a potential pharmacophore for tumor therapy in the future.


Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Antineoplásicos/farmacología , Gastrópodos/química , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Péptidos/farmacología , Residuos/análisis , Inhibidores de la Angiogénesis/química , Inhibidores de la Angiogénesis/aislamiento & purificación , Animales , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , Metástasis de la Neoplasia , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Neovascularización Patológica/fisiopatología , Péptidos/química , Péptidos/aislamiento & purificación , Mariscos/análisis , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo
7.
Oxid Med Cell Longev ; 2019: 2304018, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31178954

RESUMEN

Angiogenesis is the process of new vessel formation, which sprouts from preexisting vessels. This process is highly complex and primarily involves several key steps, including stimulation of endothelial cells by growth factors, degradation of the extracellular matrix by proteolytic enzymes, migration and proliferation of endothelial cells, and capillary tube formation. Currently, it is considered that multiple cytokines play a vital role in this process, which consist of proangiogenic factors (e.g., vascular endothelial growth factor, fibroblast growth factors, and angiopoietins) and antiangiogenic factors (e.g., endostatin, thrombospondin, and angiostatin). Angiogenesis is essential for most physiological events, such as body growth and development, tissue repair, and wound healing. However, uncontrolled neovascularization may contribute to angiogenic disorders. In physiological conditions, the above promoters and inhibitors function in a coordinated way to induce and sustain angiogenesis within a limited period of time. Conversely, the imbalance between proangiogenic and antiangiogenic factors could cause pathological angiogenesis and trigger several diseases. With insights into the molecular mechanisms of angiogenesis, increasing reports have shown that a close relationship exists between angiogenesis and oxidative stress (OS) in both physiological and pathological conditions. OS, an imbalance between prooxidant and antioxidant systems, is a cause and consequence of many vascular complains and serves as one of the biomarkers for these diseases. Furthermore, emerging evidence supports that OS and angiogenesis play vital roles in many dermatoses, such as psoriasis, atopic dermatitis, and skin tumor. This review summarizes recent findings on the role of OS as a trigger of angiogenesis in skin disorders, highlights newly identified mechanisms, and introduces the antiangiogenic and antioxidant therapeutic strategies.


Asunto(s)
Neovascularización Patológica/fisiopatología , Enfermedades de la Piel/fisiopatología , Humanos , Oxidación-Reducción , Estrés Oxidativo
8.
Cells ; 8(6)2019 05 30.
Artículo en Inglés | MEDLINE | ID: mdl-31151284

RESUMEN

Background: Angiogenesis inhibitors (AIs) have become established as an effective cancer treatment. Whereas their interactions with antineoplastic drugs have extensively been investigated, little is known of the effect of their co-administration with nutraceuticals/dietary supplements (N/DSs), which are often self-prescribed. N/DSs comprise a wide range of products such as herbs, nutrients, vitamins, minerals, and probiotics. Assessment of their interactions with cancer drugs, particularly AIs, is hampered by the difficulty of gauging the amount of active substances patients actually take. Moreover, there is no agreement on which approach should be used to determine which N/DSs are most likely to influence AI treatment efficacy. We present a comprehensive review of the metabolic routes of the major AIs and their possible interactions with N/DSs. Methods: The PubMed and Cochrane databases were searched for papers describing the metabolic routes of the main AIs and N/DSs. Results: Data from the 133 studies thus identified were used to compile a diagnostic table reporting known and expected AI-N/DS interactions based on their metabolization pathways. AIs and N/DSs sharing the cytochrome P450 pathway are at risk of negative interactions. Conclusions: Recent advances in pharmacogenetics offer exceptional opportunities to identify prognostic and predictive markers to enhance the efficacy of individualized AI treatments. The table provides a guide to genotyping patients who are due to receive AIs and is a promising tool to prevent occult AI-N/DS interactions in poor metabolizers. N/DS use by cancer patients receiving AIs is a topical problem requiring urgent attention from the scientific community.


Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Suplementos Dietéticos , Interacciones de Drogas , Farmacogenética , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Humanos , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/fisiopatología , Factor A de Crecimiento Endotelial Vascular/genética
9.
Cells ; 8(5)2019 05 17.
Artículo en Inglés | MEDLINE | ID: mdl-31108880

RESUMEN

Angiopoietins 1-4 (Ang1-4) represent an important family of growth factors, whose activities are mediated through the tyrosine kinase receptors, Tie1 and Tie2. The best characterized are angiopoietin-1 (Ang1) and angiopoietin-2 (Ang2). Ang1 is a potent angiogenic growth factor signaling through Tie2, whereas Ang2 was initially identified as a vascular disruptive agent with antagonistic activity through the same receptor. Recent data demonstrates that Ang2 has context-dependent agonist activities. Ang2 plays important roles in physiological processes and the deregulation of its expression is characteristic of several diseases. In this review, we summarize the activity of Ang2 on blood and lymphatic endothelial cells, its significance in human physiology and disease, and provide a current view of the molecular signaling pathways regulated by Ang2 in endothelial cells.


Asunto(s)
Angiopoyetina 2/metabolismo , Permeabilidad Capilar , Neovascularización Patológica/fisiopatología , Neovascularización Fisiológica/fisiología , Animales , Biomarcadores de Tumor/metabolismo , Células Endoteliales/metabolismo , Endotelio Linfático/citología , Endotelio Vascular/citología , Humanos , Inflamación/metabolismo , Ratones , Receptor TIE-1/metabolismo , Receptor TIE-2/metabolismo
10.
Dig Dis ; 37(6): 498-508, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31067534

RESUMEN

BACKGROUND/AIMS: One hallmark of chronic liver disease in patients with portal hypertension is the formation of portal-systemic collaterals in which angiogenesis has a fundamental role. We studied patients with chronic liver disease undergoing liver transplantation to correlate levels of circulating angiogenic factors in portal and peripheral circulation with portal pressure and portal-systemic collaterals. METHODS: Sixteen patients who underwent liver transplantation were enrolled. During transplant surgery, we determined portal venous pressure and portal-systemic collateral formation. We determined angiogenics mediator levels in systemic and portal plasma. Peripheral plasma from healthy donors was measured as controls. RESULTS: Vascular endothelial growth factor (VEGF)-R1 and 2, Ang-1 and 2, Tie2, FGF- 1 and 2, CD163, PDGFR-ß, PDGFsRα, PDGF-AB and BB, CD163, TGF-ß VASH-1 levels were significantly different in the controls in comparison to cases. Significantly decreased portal venous levels of Ang-1, FGF-1, PDGF-AB/BB, and CC were observed in patients with higher portal pressure. Peripheral VEGF, Ang-1, pPDGF-AB, BB, and CC were significantly decreased in patients with more severe collateral formation. While peripheral VEGF-R1 was higher in patients with severe collateral formation. For portal circulation, VEGF, Ang-1, -pPDGF-AB, BB, and CC were significantly decreased in patients with more severe collateral formation Conclusions: Angiogenesis factors correlated with portal pressure and collateral formation and different patterns of circulating angiogenesis mediators were found in peripheral and portal blood of patients with chronic liver disease. These results support the importance of angiogenic pathways in cirrhosis and portal hypertension and highlight areas for further study to identify clinically useful noninvasive markers of portal pressure and collateral formation.


Asunto(s)
Circulación Colateral , Hepatopatías/fisiopatología , Neovascularización Patológica/patología , Presión Portal , Adulto , Anciano , Animales , Enfermedad Crónica , Femenino , Humanos , Hígado/patología , Trasplante de Hígado , Masculino , Persona de Mediana Edad , Neovascularización Patológica/fisiopatología , Donantes de Tejidos
11.
BMC Bioinformatics ; 20(Suppl 7): 203, 2019 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-31074391

RESUMEN

BACKGROUND: Experimental studies have demonstrated that both the extracellular vasculature or microenvironment and intracellular molecular network (e.g., epidermal growth factor receptor (EGFR) signaling pathway) are important for brain tumor growth. Additionally, some drugs have been developed to inhibit EGFR signaling pathways. However, how angiogenesis affects the response of tumor cells to drug treatment has rarely been mechanistically studied. Therefore, a multiscale model is required to investigate such complex biological systems that contain interactions and feedback among multiple levels. RESULTS: In this study, we developed a single cell-based multiscale spatiotemporal model to simulate vascular tumor growth and the drug response based on the vascular endothelial growth factor receptor (VEGFR) signaling pathway, the EGFR signaling pathway and the cell cycle as well as several microenvironmental factors that determine cell fate switches in a temporal and spatial context. By incorporating the EGFRI treatment effect, the model showed an interesting phenomenon in which the survival rate of tumor cells decreased in the early stage but rebounded in a later stage, revealing the emergence of drug resistance. Moreover, we revealed the critical role of angiogenesis in acquired drug resistance, since inhibiting blood vessel growth using a VEGFR inhibitor prevented the recovery of the survival rate of tumor cells in the later stage. We further investigated the optimal timing of combining VEGFR inhibition with EGFR inhibition and predicted that the drug combination targeting both the EGFR pathway and VEGFR pathway has a synergistic effect. The experimental data validated the prediction of drug synergy, confirming the effectiveness of our model. In addition, the combination of EGFR and VEGFR genes showed clinical relevance in glioma patients. CONCLUSIONS: The developed multiscale model revealed angiogenesis-induced drug resistance mechanisms of brain tumors to EGFRI treatment and predicted a synergistic drug combination targeting both EGFR and VEGFR pathways with optimal combination timing. This study explored the mechanistic and functional mechanisms of the angiogenesis underlying tumor growth and drug resistance, which advances our understanding of novel mechanisms of drug resistance and provides implications for designing more effective cancer therapies.


Asunto(s)
Neoplasias Encefálicas/tratamiento farmacológico , Resistencia a Antineoplásicos , Modelos Estadísticos , Neovascularización Patológica/fisiopatología , Inhibidores de Proteínas Quinasas/farmacología , Receptor 1 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Neoplasias Encefálicas/irrigación sanguínea , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Combinación de Medicamentos , Sinergismo Farmacológico , Receptores ErbB/antagonistas & inhibidores , Humanos , Pronóstico , Transducción de Señal/efectos de los fármacos , Tasa de Supervivencia , Microambiente Tumoral
12.
Food Funct ; 10(5): 2605-2617, 2019 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-31020299

RESUMEN

The rhizome of Alpinia officinarum Hance, a popular spice used as a condiment in China and Europe, has various reported bioactivities, including anticancer, anti-inflammatory and antioxidant effects. However, its anti-angiogenic activity has not previously been reported. In this study, a diarylheptanoid was isolated from Alpinia officinarum and identified as 1-phenyl-7-(4-hydroxy-3-methoxyphenyl)-4E-en-3-heptanone (PHMH). We demonstrated that PHMH exerts anti-angiogenic activity both in vitro and in vivo. PHMH inhibited vascular endothelial growth factor (VEGF)-induced viability, migration, invasion and tube formation in human umbilical vein endothelial cells (HUVECs) in vitro, and also suppressed VEGF-induced sprout formation of rat aorta ex vivo. Furthermore, PHMH was found to block VEGF-induced vessel formation in mice and suppress angiogenesis in both zebrafish and chorioallantoic membrane models. Mechanistic studies indicated that PHMH inhibited VEGF-induced VEGF receptor-2 (VEGFR-2) auto-phosphorylation and resulted in the blockage of VEGFR-2-mediated signaling cascades in HUVECs, including the Akt/mTOR, ERK1/2, and FAK pathways. Our findings provide new insights into the potential application of PHMH as a therapeutic agent for anti-angiogenesis.


Asunto(s)
Inhibidores de la Angiogénesis/administración & dosificación , Diarilheptanoides/administración & dosificación , Medicamentos Herbarios Chinos/administración & dosificación , Neovascularización Patológica/tratamiento farmacológico , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Alpinia , Inhibidores de la Angiogénesis/química , Animales , Movimiento Celular/efectos de los fármacos , China , Diarilheptanoides/química , Medicamentos Herbarios Chinos/química , Femenino , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Masculino , Ratones Endogámicos C57BL , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Neovascularización Patológica/fisiopatología , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Pez Cebra
13.
Nitric Oxide ; 87: 52-59, 2019 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-30862477

RESUMEN

S-nitrosylation, the modification by nitric oxide of free sulfhydryl groups in cysteines, has become an important regulatory mechanism in carcinogenesis and metastasis. S-nitrosylation of targets in tumor cells contributes to metastasis regulating epithelial to mesenchymal transition, migration and invasion. In the tumor environment, the role of S-nitrosylation in endothelium has not been addressed; however, the evidence points out that S-nitrosylation of endothelial proteins may regulate angiogenesis, adhesion of tumor cells to the endothelium, intra and extravasation of tumor cells and contribute to metastasis.


Asunto(s)
Neoplasias de la Mama/metabolismo , Metástasis de la Neoplasia/fisiopatología , Neovascularización Patológica/fisiopatología , Proteínas/metabolismo , Animales , Endotelio Vascular/metabolismo , Humanos , Nitratos/metabolismo , Nitrosación , Proteínas/química
14.
Arterioscler Thromb Vasc Biol ; 39(4): 603-612, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30727757

RESUMEN

Smooth muscle cells (SMCs) are a critical component of blood vessel walls that provide structural support, regulate vascular tone, and allow for vascular remodeling. These cells also exhibit a remarkable plasticity that contributes to vascular growth and repair but also to cardiovascular pathologies, including atherosclerosis, intimal hyperplasia and restenosis, aneurysm, and transplant vasculopathy. Mouse models have been an important tool for the study of SMC functions. The development of smooth muscle-expressing Cre-driver lines has allowed for exciting discoveries, including recent advances revealing the diversity of phenotypes derived from mature SMC transdifferentiation in vivo using inducible CreER T2 lines. We review SMC-targeting Cre lines driven by the Myh11, Tagln, and Acta2 promoters, including important technical considerations associated with these models. Limitations that can complicate study of the vasculature include expression in visceral SMCs leading to confounding phenotypes, and expression in multiple nonsmooth muscle cell types, such as Acta2-Cre expression in myofibroblasts. Notably, the frequently employed Tagln/ SM22α- Cre driver expresses in the embryonic heart but can also confer expression in nonmuscular cells including perivascular adipocytes and their precursors, myeloid cells, and platelets, with important implications for interpretation of cardiovascular phenotypes. With new Cre-driver lines under development and the increasing use of fate mapping methods, we are entering an exciting new era in SMC research.


Asunto(s)
Marcación de Gen/métodos , Músculo Liso Vascular/fisiología , Regiones Promotoras Genéticas , Actinas/biosíntesis , Actinas/genética , Animales , Línea Celular , Linaje de la Célula , Transdiferenciación Celular , Regulación de la Expresión Génica , Técnicas de Inactivación de Genes , Humanos , Ratones , Proteínas de Microfilamentos/biosíntesis , Proteínas de Microfilamentos/genética , Proteínas Musculares/biosíntesis , Proteínas Musculares/genética , Miocitos del Músculo Liso/fisiología , Miofibroblastos/fisiología , Cadenas Pesadas de Miosina/biosíntesis , Cadenas Pesadas de Miosina/genética , Neovascularización Patológica/fisiopatología , Neovascularización Fisiológica , Fenotipo , Proteínas Recombinantes de Fusión/metabolismo
15.
Arterioscler Thromb Vasc Biol ; 39(4): 635-646, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30786744

RESUMEN

Nanoparticles promise to advance strategies to treat vascular disease. Since being harnessed by the cancer field to deliver safer and more effective chemotherapeutics, nanoparticles have been translated into applications for cardiovascular disease. Systemic exposure and drug-drug interactions remain a concern for nearly all cardiovascular therapies, including statins, antithrombotic, and thrombolytic agents. Moreover, off-target effects and poor bioavailability have limited the development of completely new approaches to treat vascular disease. Through the rational design of nanoparticles, nano-based delivery systems enable more efficient delivery of a drug to its therapeutic target or even directly to the diseased site, overcoming biological barriers and enhancing a drug's therapeutic index. In addition, advances in molecular imaging have led to the development of theranostic nanoparticles that may simultaneously act as carriers of both therapeutic and imaging payloads. The following is a summary of nanoparticle therapy for atherosclerosis, thrombosis, and restenosis and an overview of recent major advances in the targeted treatment of vascular disease.


Asunto(s)
Fármacos Cardiovasculares/administración & dosificación , Portadores de Fármacos/administración & dosificación , Nanopartículas/administración & dosificación , Enfermedades Vasculares/tratamiento farmacológico , Animales , Quimiotaxis de Leucocito/efectos de los fármacos , Colesterol/metabolismo , Evaluación Preclínica de Medicamentos , Predicción , Humanos , Inflamación/tratamiento farmacológico , Macrófagos/efectos de los fármacos , Ratones , Neointima/tratamiento farmacológico , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/fisiopatología , Placa Aterosclerótica/fisiopatología , Interferencia de ARN , ARN Interferente Pequeño/farmacología , Trombosis/tratamiento farmacológico
16.
J Agric Food Chem ; 67(10): 2856-2864, 2019 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-30785275

RESUMEN

Among the various treatments, induction of synoviocyte apoptosis by natural products during a rheumatoid arthritis (RA) pathological condition can be considered to have vast potential. However, it is unclear that liquiritin, a kind of natural flavonoid extracted from the roots of Glycyrrhiza uralensis, induced the apoptosis of the synovial membrane and its molecular mechanism. In this study, interleukin-1ß (IL-1ß)-RA-FLS cells were incubated with different concentrations of liquiritin. An MTT assay, Hoechst 33342 staining, JC-1 staining, and Western blot were used to check the viability, cell apoptosis, mitochondrial membrane potential changes, and the expression of related proteins, respectively. In vivo, a TUNEL assay and HE staining of tissue were used for histopathological evaluation. Our results showed that liquiritin significantly inhibited the proliferation of IL-1ß-induced-RA-FLS, promoted nuclear DNA fragmentation, and changed the mitochondrial membrane potential to accelerate cell apoptosis. Liquiritin downregulated the ratio of Bcl-2/Bax and inhibited the VEGF expression and phosphorylation of JNK and P38. Moreover, liquiritin improved the clinical score of rheumatism, inflammatory infiltration, and angiogenesis and induced apoptosis of the synovial tissue in vivo. Hence, liquiritin ameliorates RA by reducing inflammation, blocking MAPK signaling, and restraining angiogenesis.


Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/inmunología , Medicamentos Herbarios Chinos/administración & dosificación , Flavanonas/administración & dosificación , Glucósidos/administración & dosificación , Glycyrrhiza uralensis/química , Neovascularización Patológica/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Artritis Reumatoide/genética , Artritis Reumatoide/fisiopatología , Proliferación Celular/efectos de los fármacos , Humanos , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Neovascularización Patológica/genética , Neovascularización Patológica/inmunología , Neovascularización Patológica/fisiopatología , Fosforilación/efectos de los fármacos , Ratas , Ratas Wistar , Membrana Sinovial/efectos de los fármacos , Membrana Sinovial/inmunología , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas Quinasas p38 Activadas por Mitógenos/inmunología
17.
Am J Physiol Heart Circ Physiol ; 316(4): H900-H910, 2019 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-30707613

RESUMEN

Although increased levels of reactive oxygen species (ROS) are involved in the pathogenesis of cardiovascular diseases, the importance of physiological ROS has also been emerging. We have previously demonstrated that endothelium-derived H2O2 is an endothelium-dependent hyperpolarization (EDH) factor and that loss of endothelial caveolin-1 reduces EDH/H2O2 in the microcirculation. Caveolin-1 (Cav-1) is a scaffolding/regulatory protein that interacts with diverse signaling pathways, including angiogenesis. However, it remains unclear whether endothelial Cav-1 plays a role in ischemic angiogenesis by modulating EDH/H2O2. In the present study, we thus addressed this issue in a mouse model of hindlimb ischemia using male endothelium-specific Cav-1 (eCav-1) knockout (KO) mice. In isometric tension experiments with femoral arteries from eCav-1-KO mice, reduced EDH-mediated relaxations to acetylcholine and desensitization of sodium nitroprusside-mediated endothelium-independent relaxations were noted ( n = 4~6). An ex vivo aortic ring assay also showed that the extent of microvessel sprouting was significantly reduced in eCav-1-KO mice compared with wild-type (WT) littermates ( n = 12 each). Blood flow recovery at 4 wk assessed with a laser speckle flowmeter after femoral artery ligation was significantly impaired in eCav-1-KO mice compared with WT littermates ( n = 10 each) and was associated with reduced capillary density and muscle fibrosis in the legs ( n = 6 each). Importantly, posttranslational protein modifications by reactive nitrogen species and ROS, as evaluated by thiol glutathione adducts and nitrotyrosine, respectively, were both increased in eCav-1-KO mice ( n = 6~7 each). These results indicate that endothelial Cav-1 plays an important role in EDH-mediated vasodilatation and ischemic angiogenesis through posttranslational protein modifications by nitrooxidative stress in mice in vivo. NEW & NOTEWORTHY Although increased levels of reactive oxygen species (ROS) are involved in the pathogenesis of cardiovascular diseases, the importance of physiological ROS has also been emerging. The present study provides a line of novel evidence that endothelial caveolin-1 plays important roles in endothelium-dependent hyperpolarization and ischemic angiogenesis in hindlimb ischemia in mice through posttranslational protein modifications by reactive nitrogen species and ROS in mice in vivo.


Asunto(s)
Caveolina 1/metabolismo , Endotelio Vascular/metabolismo , Neovascularización Patológica/fisiopatología , Animales , Caveolina 1/genética , Arteria Femoral/fisiopatología , Miembro Posterior/irrigación sanguínea , Peróxido de Hidrógeno/metabolismo , Isquemia/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Estrés Oxidativo , Procesamiento Proteico-Postraduccional , Especies de Nitrógeno Reactivo , Especies Reactivas de Oxígeno/metabolismo , Flujo Sanguíneo Regional , Vasodilatación
18.
Am J Med Sci ; 357(4): 280-288, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30711189

RESUMEN

In this review, we discuss the pathologic mechanism of the angiogenesis process in osteosarcoma (OS) and the therapeutic use of angiogenesis inhibitors in OS treatment. The activation of endothelial cells by angiogenic factors leads to the production of proteolytic enzymes, which degrade the extracellular matrix. The degradation of the underlying basement membrane enables endothelial cells to proliferate and migrate to the surrounding tissue to form new vessels. These new vessels provide cancer cells with oxygen and nutrition and play an important role in cancer cell survival and metastasis. Thus, antiangiogenic therapies might be an interesting approach in OS therapeutics.


Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Neovascularización Patológica , Osteosarcoma , Humanos , Neovascularización Patológica/fisiopatología , Neovascularización Patológica/terapia , Osteosarcoma/fisiopatología , Osteosarcoma/terapia
19.
J Vis Exp ; (143)2019 01 25.
Artículo en Inglés | MEDLINE | ID: mdl-30735169

RESUMEN

Diabetic retinopathy (DR) is the most common microvascular complication of diabetes and one of the leading causes of blindness in working-age adults. No current animal models of diabetes and oxygen-induced retinopathy develop the full-range progressive changes manifested in human proliferative diabetic retinopathy (PDR). Therefore, understanding of the disease pathogenesis and pathophysiology has relied largely on the use of histological sections and vitreous samples in approaches that only provide steady-state information on the involved pathogenic factors. Increasing evidence indicates that dynamic cell-cell and cell-extracellular matrix (ECM) interactions in the context of three-dimensional (3D) microenvironments are essential for the mechanistic and functional studies towards the development of new treatment strategies. Therefore, we hypothesized that the pathological fibrovascular tissue surgically excised from eyes with PDR could be utilized to reliably unravel the cellular and molecular mechanisms of this devastating disease and to test the potential for novel clinical interventions. Towards this end, we developed a novel method for 3D ex vivo culture of surgically-excised patient-derived fibrovascular tissue (FT), which will serve as a relevant model of human PDR pathophysiology. The FTs are dissected into explants and embedded in fibrin matrix for ex vivo culture and 3D characterization. Whole-mount immunofluorescence of the native FTs and end-point cultures allows thorough investigation of tissue composition and multicellular processes, highlighting the importance of 3D tissue-level characterization for uncovering relevant features of PDR pathophysiology. This model will allow the simultaneous assessment of molecular mechanisms, cellular/tissue processes and treatment responses in the complex context of dynamic biochemical and physical interactions within the PDR tissue architecture and microenvironment. Since this model recapitulates PDR pathophysiology, it will also be amenable for testing or developing new treatments.


Asunto(s)
Proliferación Celular , Retinopatía Diabética/complicaciones , Modelos Biológicos , Neovascularización Patológica/fisiopatología , Neovascularización Retiniana/fisiopatología , Cuerpo Vítreo/fisiopatología , Diferenciación Celular , Células Cultivadas , Humanos , Neovascularización Patológica/etiología , Neovascularización Retiniana/etiología
20.
Am J Physiol Heart Circ Physiol ; 316(1): H245-H254, 2019 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-30444664

RESUMEN

Inadequate perfusion of solid cancer tissue results in low local nutrient and oxygen levels and accumulation of acidic waste products. Previous investigations have focused primarily on tumor blood vessel architecture, and we lack information concerning functional differences between arteries that deliver blood to solid cancer tissue versus normal tissue. Here, we use isometric myography to study resistance-sized arteries from human primary colon adenocarcinomas and matched normal colon tissue. Vasocontraction of colon cancer feed arteries in response to endothelin-1 and thromboxane stimulation is attenuated compared with normal colon arteries despite similar wall dimensions and comparable contractions to arginine vasopressin and K+-induced depolarization. Acetylcholine-induced vasorelaxation and endothelial NO synthase expression are increased in colon cancer feed arteries compared with normal colon arteries, whereas vasorelaxation to exogenous NO donors is unaffected. In congruence, the differences in vasorelaxant and vasocontractile function between colon cancer feed arteries and normal colon arteries decrease after NO synthase inhibition. Rhythmic oscillations in vascular tone, known as vasomotion, are of lower amplitude but similar frequency in colon cancer feed arteries compared with normal colon arteries. In conclusion, higher NO synthase expression and elevated NO signaling amplify vasorelaxation and attenuate vasocontraction of human colon cancer feed arteries. We propose that enhanced endothelial function augments tumor perfusion and represents a potential therapeutic target. NEW & NOTEWORTHY Local vascular resistance influences tumor perfusion. Arteries supplying human colonic adenocarcinomas show enhanced vasorelaxation and reduced vasocontraction mainly due to elevated nitric oxide-mediated signaling. Rhythmic oscillations in tone, known as vasomotion, are attenuated in colon cancer feed arteries.


Asunto(s)
Adenocarcinoma/patología , Arterias/metabolismo , Neoplasias del Colon/patología , Neovascularización Patológica/metabolismo , Óxido Nítrico/metabolismo , Vasodilatación , Acetilcolina/farmacología , Adulto , Anciano , Anciano de 80 o más Años , Arterias/efectos de los fármacos , Arterias/fisiopatología , Endotelina-1/farmacología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neovascularización Patológica/fisiopatología , Óxido Nítrico Sintasa de Tipo III/metabolismo , Transducción de Señal , Tromboxanos/farmacología , Vasoconstrictores/farmacología , Vasodilatadores/farmacología
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