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1.
Nat Immunol ; 18(6): 654-664, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28414311

RESUMEN

In obesity, inflammation of white adipose tissue (AT) is associated with diminished generation of beige adipocytes ('beige adipogenesis'), a thermogenic and energy-dissipating function mediated by beige adipocytes that express the uncoupling protein UCP1. Here we delineated an inflammation-driven inhibitory mechanism of beige adipogenesis in obesity that required direct adhesive interactions between macrophages and adipocytes mediated by the integrin α4 and its counter-receptor VCAM-1, respectively; expression of the latter was upregulated in obesity. This adhesive interaction reciprocally and concomitantly modulated inflammatory activation of macrophages and downregulation of UCP1 expression dependent on the kinase Erk in adipocytes. Genetic or pharmacological inactivation of the integrin α4 in mice resulted in elevated expression of UCP1 and beige adipogenesis of subcutaneous AT in obesity. Our findings, established in both mouse systems and human systems, reveal a self-sustained cycle of inflammation-driven impairment of beige adipogenesis in obesity.


Asunto(s)
Adipocitos Beige , Adipogénesis/inmunología , Tejido Adiposo Blanco/inmunología , Diferenciación Celular/inmunología , Inflamación/inmunología , Macrófagos/inmunología , Obesidad/inmunología , Células 3T3-L1 , Adipocitos/inmunología , Adipocitos/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Animales , Adhesión Celular/inmunología , Dieta Alta en Grasa , Regulación hacia Abajo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Retroalimentación , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Immunoblotting , Integrina alfa4/genética , Macrófagos/metabolismo , Masculino , Ratones , Persona de Mediana Edad , Monocitos/inmunología , Obesidad/metabolismo , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Grasa Subcutánea , Linfocitos T/inmunología , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo , Molécula 1 de Adhesión Celular Vascular/genética , Molécula 1 de Adhesión Celular Vascular/metabolismo , Adulto Joven
2.
J Neurochem ; 153(3): 390-412, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-31550048

RESUMEN

Retinal hypoxia triggers abnormal vessel growth and microvascular hyper-permeability in ischemic retinopathies. Whereas vascular endothelial growth factor A (VEGF-A) inhibitors significantly hinder disease progression, their benefits to retinal neurons remain poorly understood. Similar to humans, oxygen-induced retinopathy (OIR) mice exhibit severe retinal microvascular malformations and profound neuronal dysfunction. OIR mice are thus a phenocopy of human retinopathy of prematurity, and a proxy for investigating advanced stages of proliferative diabetic retinopathy. Hence, the OIR model offers an excellent platform for assessing morpho-functional responses of the ischemic retina to anti-angiogenic therapies. Using this model, we investigated the retinal responses to VEGF-Trap (Aflibercept), an anti-angiogenic agent recognizing ligands of VEGF receptors 1 and 2 that possesses regulatory approval for the treatment of neovascular age-related macular degeneration, macular edema secondary to retinal vein occlusion and diabetic macular edema. Our results indicate that Aflibercept not only reduces the severity of retinal microvascular aberrations but also significantly improves neuroretinal function. Aflibercept administration significantly enhanced light-responsiveness, as revealed by electroretinographic examinations, and led to increased numbers of dopaminergic amacrine cells. Additionally, retinal transcriptional profiling revealed the concerted regulation of both angiogenic and neuronal targets, including transcripts encoding subunits of transmitter receptors relevant to amacrine cell function. Thus, Aflibercept represents a promising therapeutic alternative for the treatment of further progressive ischemic retinal neurovasculopathies beyond the set of disease conditions for which it has regulatory approval. Cover Image for this issue: doi: 10.1111/jnc.14743.


Asunto(s)
Neuronas Dopaminérgicas/efectos de los fármacos , Microvasos/efectos de los fármacos , Red Nerviosa/efectos de los fármacos , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Degeneración Retiniana/tratamiento farmacológico , Vasos Retinianos/efectos de los fármacos , Animales , Animales Recién Nacidos , Neuronas Dopaminérgicas/patología , Femenino , Isquemia/tratamiento farmacológico , Isquemia/patología , Masculino , Ratones , Microvasos/patología , Red Nerviosa/patología , Proteínas Recombinantes de Fusión/farmacología , Degeneración Retiniana/patología , Vasos Retinianos/patología , Sistema Vasomotor/efectos de los fármacos , Sistema Vasomotor/patología
3.
J Cell Mol Med ; 23(4): 2362-2371, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30680928

RESUMEN

The mechanism underlying vasoproliferative retinopathies like retinopathy of prematurity (ROP) is hypoxia-triggered neovascularisation. Nerve growth factor (NGF), a neurotrophin supporting survival and differentiation of neuronal cells may also regulate endothelial cell functions. Here we studied the role of NGF in pathological retinal angiogenesis in the course of the ROP mouse model. Topical application of NGF enhanced while intraocular injections of anti-NGF neutralizing antibody reduced pathological retinal vascularization in mice subjected to the ROP model. The pro-angiogenic effect of NGF in the retina was mediated by inhibition of retinal endothelial cell apoptosis. In vitro, NGF decreased the intrinsic (mitochondria-dependent) apoptosis in hypoxia-treated human retinal microvascular endothelial cells and preserved the mitochondrial membrane potential. The anti-apoptotic effect of NGF was associated with increased BCL2 and reduced BAX, as well as with enhanced ERK and AKT phosphorylation, and was abolished by inhibition of the AKT pathway. Our findings reveal an anti-apoptotic role of NGF in the hypoxic retinal endothelium, which is involved in promoting pathological retinal vascularization, thereby pointing to NGF as a potential target for proliferative retinopathies.


Asunto(s)
Anticuerpos Neutralizantes/farmacología , Neovascularización Patológica/terapia , Factor de Crecimiento Nervioso/antagonistas & inhibidores , Retinopatía de la Prematuridad/terapia , Apoptosis/efectos de los fármacos , Células Endoteliales , Humanos , Inyecciones Intraoculares , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Neovascularización Patológica/genética , Neovascularización Patológica/patología , Factor de Crecimiento Nervioso/genética , Neuronas/efectos de los fármacos , Neuronas/patología , Proteínas Proto-Oncogénicas c-bcl-2/genética , Retina/efectos de los fármacos , Retina/patología , Retinopatía de la Prematuridad/genética , Retinopatía de la Prematuridad/patología , Proteína X Asociada a bcl-2/genética
4.
Mol Psychiatry ; 20(7): 880-888, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25385367

RESUMEN

Inflammation in the central nervous system (CNS) and disruption of its immune privilege are major contributors to the pathogenesis of multiple sclerosis (MS) and of its rodent counterpart, experimental autoimmune encephalomyelitis (EAE). We have previously identified developmental endothelial locus-1 (Del-1) as an endogenous anti-inflammatory factor, which inhibits integrin-dependent leukocyte adhesion. Here we show that Del-1 contributes to the immune privilege status of the CNS. Intriguingly, Del-1 expression decreased in chronic-active MS lesions and in the inflamed CNS in the course of EAE. Del-1-deficiency was associated with increased EAE severity, accompanied by increased demyelination and axonal loss. As compared with control mice, Del-1(-/-) mice displayed enhanced disruption of the blood-brain barrier and increased infiltration of neutrophil granulocytes in the spinal cord in the course of EAE, accompanied by elevated levels of inflammatory cytokines, including interleukin-17 (IL-17). The augmented levels of IL-17 in Del-1-deficiency derived predominantly from infiltrated CD8(+) T cells. Increased EAE severity and neutrophil infiltration because of Del-1-deficiency was reversed in mice lacking both Del-1 and IL-17 receptor, indicating a crucial role for the IL-17/neutrophil inflammatory axis in EAE pathogenesis in Del-1(-/-) mice. Strikingly, systemic administration of Del-1-Fc ameliorated clinical relapse in relapsing-remitting EAE. Therefore, Del-1 is an endogenous homeostatic factor in the CNS protecting from neuroinflammation and demyelination. Our findings provide mechanistic underpinnings for the previous implication of Del-1 as a candidate MS susceptibility gene and suggest that Del-1-centered therapeutic approaches may be beneficial in neuroinflammatory and demyelinating disorders.


Asunto(s)
Axones/metabolismo , Barrera Hematoencefálica/metabolismo , Proteínas Portadoras/metabolismo , Vaina de Mielina/metabolismo , Neuroinmunomodulación/fisiología , Médula Espinal/metabolismo , Animales , Axones/efectos de los fármacos , Axones/patología , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/patología , Proteínas de Unión al Calcio , Permeabilidad Capilar/efectos de los fármacos , Permeabilidad Capilar/fisiología , Proteínas Portadoras/genética , Moléculas de Adhesión Celular , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/metabolismo , Encefalomielitis Autoinmune Experimental/patología , Femenino , Granulocitos/efectos de los fármacos , Granulocitos/metabolismo , Granulocitos/patología , Homeostasis/efectos de los fármacos , Homeostasis/fisiología , Péptidos y Proteínas de Señalización Intercelular , Interleucina-17/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Vaina de Mielina/efectos de los fármacos , Vaina de Mielina/patología , Neuroinmunomodulación/efectos de los fármacos , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Neutrófilos/patología , Receptores de Interleucina-17/genética , Receptores de Interleucina-17/metabolismo , Índice de Severidad de la Enfermedad , Médula Espinal/efectos de los fármacos , Médula Espinal/patología
5.
J Immunol ; 191(8): 4367-74, 2013 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-24043887

RESUMEN

Obese adipose tissue (AT) inflammation contributes critically to development of insulin resistance. The complement anaphylatoxin C5a receptor (C5aR) has been implicated in inflammatory processes and as regulator of macrophage activation and polarization. However, the role of C5aR in obesity and AT inflammation has not been addressed. We engaged the model of diet-induced obesity and found that expression of C5aR was significantly upregulated in the obese AT, compared with lean AT. In addition, C5a was present in obese AT in the proximity of macrophage-rich crownlike structures. C5aR-sufficient and -deficient mice were fed a high-fat diet (HFD) or a normal diet (ND). C5aR deficiency was associated with increased AT weight upon ND feeding in males, but not in females, and with increased adipocyte size upon ND and HFD conditions in males. However, obese C5aR(-/-) mice displayed improved systemic and AT insulin sensitivity. Improved AT insulin sensitivity in C5aR(-/-) mice was associated with reduced accumulation of total and proinflammatory M1 macrophages in the obese AT, increased expression of IL-10, and decreased AT fibrosis. In contrast, no difference in ß cell mass was observed owing to C5aR deficiency under an HFD. These results suggest that C5aR contributes to macrophage accumulation and M1 polarization in the obese AT and thereby to AT dysfunction and development of AT insulin resistance.


Asunto(s)
Tejido Adiposo/inmunología , Tejido Adiposo/metabolismo , Resistencia a la Insulina/inmunología , Macrófagos/inmunología , Receptor de Anafilatoxina C5a/metabolismo , Adipocitos/inmunología , Adipocitos/metabolismo , Animales , Complemento C5a/metabolismo , Grasas de la Dieta/inmunología , Grasas de la Dieta/metabolismo , Femenino , Fibrosis/inmunología , Inflamación/inmunología , Células Secretoras de Insulina/metabolismo , Interleucina-10/biosíntesis , Activación de Macrófagos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Obesidad/inmunología , Obesidad/metabolismo , Receptor de Anafilatoxina C5a/biosíntesis , Receptor de Anafilatoxina C5a/inmunología , Regulación hacia Arriba
6.
Int J Cancer ; 135(9): 2054-64, 2014 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-24676840

RESUMEN

Pheochromocytomas and paragangliomas (PPGLs) are catecholamine-producing chromaffin cell tumors with diverse phenotypic features reflecting mutations in numerous genes, including MYC-associated factor X (MAX). To explore whether phenotypic differences among PPGLs reflect a MAX-mediated mechanism and opposing influences of hypoxia-inducible factor (HIF)s HIF2α and HIF1α, we combined observational investigations in PPGLs and gene-manipulation studies in two pheochromocytoma cell lines. Among PPGLs from 140 patients, tumors due to MAX mutations were characterized by gene expression profiles and intermediate phenotypic features that distinguished these tumors from other PPGLs, all of which fell into two expression clusters: one cluster with low expression of HIF2α and mature phenotypic features and the other with high expression of HIF2α and immature phenotypic features due to mutations stabilizing HIFs. Max-mutated tumors distributed to a distinct subcluster of the former group. In cell lines lacking Max, re-expression of the gene resulted in maturation of phenotypic features and decreased cell cycle progression. In cell lines lacking Hif2α, overexpression of the gene led to immature phenotypic features, failure of dexamethasone to induce differentiation and increased proliferation. HIF1α had opposing actions to HIF2α in both cell lines, supporting evolving evidence of their differential actions on tumorigenic processes via a MYC/MAX-related pathway. Requirement of a fully functional MYC/MAX complex to facilitate differentiation explains the intermediate phenotypic features in tumors due to MAX mutations. Overexpression of HIF2α in chromaffin cell tumors due to mutations affecting HIF stabilization explains their proliferative features and why the tumors fail to differentiate even when exposed locally to adrenal steroids.


Asunto(s)
Neoplasias de las Glándulas Suprarrenales/patología , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Biomarcadores de Tumor/metabolismo , Proliferación Celular , Células Cromafines/patología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Paraganglioma/patología , Feocromocitoma/patología , Neoplasias de las Glándulas Suprarrenales/genética , Neoplasias de las Glándulas Suprarrenales/metabolismo , Animales , Apoptosis , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Biomarcadores de Tumor/genética , Western Blotting , Ciclo Celular , Diferenciación Celular , Células Cromafines/metabolismo , Perfilación de la Expresión Génica , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Mutación/genética , Paraganglioma/genética , Paraganglioma/metabolismo , Feocromocitoma/genética , Feocromocitoma/metabolismo , ARN Mensajero/genética , Ratas , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Tumorales Cultivadas
7.
J Exp Med ; 203(12): 2703-14, 2006 Nov 27.
Artículo en Inglés | MEDLINE | ID: mdl-17116731

RESUMEN

We recently reported that junctional adhesion molecule (JAM)-C plays a role in leukocyte transendothelial migration. Here, the role of JAM-C in vascular permeability was investigated in vitro and in vivo. As opposed to macrovascular endothelial cells that constitutively expressed JAM-C in cell-cell contacts, in quiescent microvascular endothelial cells, JAM-C localized mainly intracellularly, and was recruited to junctions upon short-term stimulation with vascular endothelial growth factor (VEGF) or histamine. Strikingly, disruption of JAM-C function decreased basal permeability and prevented the VEGF- and histamine-induced increases in human dermal microvascular endothelial cell permeability in vitro and skin permeability in mice. Permeability increases are essential in angiogenesis, and JAM-C blockade reduced hyperpermeability and neovascularization in hypoxia-induced retinal angiogenesis in mice. The underlying mechanisms of the JAM-C-mediated increase in endothelial permeability were studied. JAM-C was essential for the regulation of endothelial actomyosin, as revealed by decreased F-actin, reduced myosin light chain phosphorylation, and actin stress fiber formation due to JAM-C knockdown. Moreover, the loss of JAM-C expression resulted in stabilization of VE-cadherin-mediated interendothelial adhesion in a manner dependent on the small GTPase Rap1. Together, through modulation of endothelial contractility and VE-cadherin-mediated adhesion, JAM-C helps to regulate vascular permeability and pathologic angiogenesis.


Asunto(s)
Antígenos CD/fisiología , Cadherinas/fisiología , Permeabilidad Capilar/fisiología , Moléculas de Adhesión Celular/fisiología , Comunicación Celular/fisiología , Endotelio Vascular/citología , Endotelio Vascular/fisiología , Animales , Antígenos CD/metabolismo , Cadherinas/metabolismo , Permeabilidad Capilar/genética , Moléculas de Adhesión Celular/deficiencia , Moléculas de Adhesión Celular/genética , Comunicación Celular/genética , Línea Celular , Drosophila/genética , Humanos , Moléculas de Adhesión de Unión , Ratones , Contracción Muscular/genética , Contracción Muscular/fisiología , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiología , Vasos Retinianos/citología , Vasos Retinianos/fisiología , Absorción Cutánea/fisiología , Factor A de Crecimiento Endotelial Vascular/administración & dosificación
8.
Blood ; 116(22): 4395-403, 2010 Nov 25.
Artículo en Inglés | MEDLINE | ID: mdl-20625009

RESUMEN

Beyond its role in immunity, complement mediates a wide range of functions in the context of morphogenetic or tissue remodeling processes. Angiogenesis is crucial during tissue remodeling in multiple pathologies; however, the knowledge about the regulation of neovascularization by the complement components is scarce. Here we studied the involvement of complement in pathological angiogenesis. Strikingly, we found that mice deficient in the central complement component C3 displayed increased neovascularization in the model of retinopathy of prematurity (ROP) and in the in vivo Matrigel plug assay. In addition, antibody-mediated blockade of C5, treatment with C5aR antagonist, or C5aR deficiency in mice resulted in enhanced pathological retina angiogenesis. While complement did not directly affect angiogenesis-related endothelial cell functions, we found that macrophages mediated the antiangiogenic activity of complement. In particular, C5a-stimulated macrophages were polarized toward an angiogenesis-inhibitory phenotype, including the up-regulated secretion of the antiangiogenic soluble vascular endothelial growth factor receptor-1. Consistently, macrophage depletion in vivo reversed the increased neovascularization associated with C3- or C5aR deficiency. Taken together, complement and in particular the C5a-C5aR axes are potent inhibitors of angiogenesis.


Asunto(s)
Complemento C3/inmunología , Complemento C5/inmunología , Inmunidad Innata , Neovascularización Patológica/inmunología , Retina/patología , Retinopatía de la Prematuridad/inmunología , Animales , Técnicas de Cultivo de Célula , Línea Celular , Complemento C3/genética , Complemento C5a/inmunología , Eliminación de Gen , Humanos , Recién Nacido , Macrófagos/inmunología , Ratones , Ratones Endogámicos C57BL , Neovascularización Patológica/patología , Receptor de Anafilatoxina C5a/genética , Receptor de Anafilatoxina C5a/inmunología , Retina/inmunología , Retinopatía de la Prematuridad/patología , Factores de Crecimiento Endotelial Vascular/inmunología
9.
Blood ; 114(8): 1707-16, 2009 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-19411631

RESUMEN

EphrinB transmembrane ligands and their cognate EphB receptor tyrosine kinases regulate vascular development through bidirectional cell-to-cell signaling, but little is known about the role of EphrinB during postnatal vascular remodeling. We report that EphrinB is a critical mediator of postnatal pericyte-to-endothelial cell assembly into vascular structures. This function is dependent upon extracellular matrix-supported cell-to-cell contact, engagement of EphrinB by EphB receptors expressed on another cell, and Src-dependent phosphorylation of the intracytoplasmic domain of EphrinB. Phosphorylated EphrinB marks angiogenic blood vessels in the developing and hypoxic retina, the wounded skin, and tumor tissue, and is detected at contact points between endothelial cells and pericytes. Furthermore, inhibition ofEphrinB activity prevents proper assembly of pericytes and endothelial cells into vascular structures. These results reveal a role for EphrinB signaling in orchestrating pericyte/endothelial cell assembly, and suggest that therapeutic targeting of EphrinB may prove useful for disrupting angiogenesis when it contributes to disease.


Asunto(s)
Vasos Sanguíneos/crecimiento & desarrollo , Células Endoteliales/fisiología , Efrinas/fisiología , Neovascularización Fisiológica/fisiología , Pericitos/fisiología , Animales , Animales Recién Nacidos , Vasos Sanguíneos/metabolismo , Células de la Médula Ósea/fisiología , Adhesión Celular/genética , Células Cultivadas , Células Endoteliales/metabolismo , Efrina-B2/antagonistas & inhibidores , Efrina-B2/genética , Efrina-B2/fisiología , Efrinas/genética , Efrinas/metabolismo , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones SCID , Neovascularización Fisiológica/genética , Pericitos/metabolismo , Receptores de la Familia Eph/genética , Receptores de la Familia Eph/metabolismo , Receptores de la Familia Eph/fisiología , Transducción de Señal/fisiología
10.
Thromb Haemost ; 119(3): 439-448, 2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-30620991

RESUMEN

The replication stress inflicted on retinal endothelial cells (ECs) in the context of hypoxia-induced pathological neovascularization during proliferative retinopathy is linked with activation of the deoxyribonucleic acid (DNA) repair response. Here, we studied the effect of deficiency of the DNA damage response adaptor 53BP1, which is an antagonist of homologous recombination (HR), in the context of proliferative retinopathy. In the model of retinopathy of prematurity (ROP), 53BP1-deficient mice displayed increased hypoxia-driven pathological neovascularization and tuft formation, accompanied by increased EC proliferation and reduced EC apoptosis, as compared with 53BP1-sufficient mice. In contrast, physiological retina angiogenesis was not affected by 53BP1 deficiency. Knockdown of 53BP1 in ECs in vitro also resulted in enhanced proliferation and reduced apoptosis of the cells under hypoxic conditions. Additionally, upon 53BP1 knockdown, ECs displayed increased HR rate in hypoxia. Consistently, treatment with an HR inhibitor reversed the hyper-proliferative angiogenic phenotype associated with 53BP1 deficiency in ROP. Thus, by unleashing HR, 53BP1 deletion increases pathological EC proliferation and neovascularization in the context of ROP. Our data shed light to a previously unknown interaction between the DNA repair response and pathological neovascularization in the retina.


Asunto(s)
Proliferación Celular , Células Endoteliales/metabolismo , Recombinación Homóloga , Neovascularización Retiniana/metabolismo , Vasos Retinianos/metabolismo , Retinopatía de la Prematuridad/metabolismo , Proteína 1 de Unión al Supresor Tumoral P53/deficiencia , Proteína 1 de Unión al Supresor Tumoral P53/metabolismo , Animales , Apoptosis , Hipoxia de la Célula , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Células Endoteliales/efectos de los fármacos , Células Endoteliales/patología , Predisposición Genética a la Enfermedad , Recombinación Homóloga/efectos de los fármacos , Humanos , Ratones Noqueados , Morfolinas/farmacología , Fenotipo , Pirroles/farmacología , Neovascularización Retiniana/genética , Neovascularización Retiniana/patología , Neovascularización Retiniana/prevención & control , Vasos Retinianos/efectos de los fármacos , Vasos Retinianos/patología , Retinopatía de la Prematuridad/genética , Retinopatía de la Prematuridad/patología , Retinopatía de la Prematuridad/prevención & control , Transducción de Señal , Proteína 1 de Unión al Supresor Tumoral P53/genética
11.
FASEB J ; 20(3): 559-61, 2006 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-16403785

RESUMEN

Lipoprotein(a) [Lp(a)], consisting of LDL and the unique constituent apolipoprotein(a) [apo(a)], which contains multiple repeats resembling plasminogen kringle 4, is considered a risk factor for the development of atherosclerotic disorders. However, the underlying mechanisms for the atherogenicity of Lp(a) are not completely understood. Here, we define a novel function of Lp(a) in promoting inflammatory cell recruitment that may contribute to its atherogenicity. Through its apo(a) moiety Lp(a) specifically interacts with the beta2-integrin Mac-1, thereby promoting the adhesion of monocytes and their transendothelial migration in a Mac-1-dependent manner. Interestingly, the interaction between Mac-1 and Lp(a) was strengthened in the presence of proatherogenic homocysteine and was blocked by plasminogen/angiostatin kringle 4. Through its interaction with Mac-1, Lp(a) induced activation of the proinflammatory transcription factor NFkappaB, as well as the NFkappaB-related expression of prothrombotic tissue factor. In atherosclerotic coronary arteries Lp(a) was found to be localized in close proximity to Mac-1 on infiltrating mononuclear cells. Taken together, our data demonstrate that Lp(a), via its apo(a) moiety, is a ligand for the beta2-integrin Mac-1, thereby facilitating inflammatory cell recruitment to atherosclerotic plaques. These observations suggest a novel mechanism for the atherogenic properties of Lp(a).


Asunto(s)
Aterosclerosis/fisiopatología , Quimiotaxis de Leucocito/fisiología , Lipoproteína(a)/fisiología , Antígeno de Macrófago-1/fisiología , Monocitos/metabolismo , Anciano , Anciano de 80 o más Años , Ácido Aminocaproico/farmacología , Angiostatinas/farmacología , Apolipoproteínas A/metabolismo , Aspirina/farmacología , Movimiento Celular , Células Cultivadas/citología , Células Cultivadas/efectos de los fármacos , Enfermedad de la Arteria Coronaria/metabolismo , Enfermedad de la Arteria Coronaria/patología , Enfermedad de la Arteria Coronaria/fisiopatología , Vasos Coronarios/química , Vasos Coronarios/patología , Células Endoteliales/citología , Células Endoteliales/metabolismo , Endotelio Vascular/citología , Femenino , Regulación de la Expresión Génica , Homocisteína/farmacología , Humanos , Molécula 1 de Adhesión Intercelular/metabolismo , Lipoproteína(a)/farmacología , Antígeno-1 Asociado a Función de Linfocito/metabolismo , Antígeno de Macrófago-1/química , Masculino , Persona de Mediana Edad , Monocitos/citología , FN-kappa B/metabolismo , Plasminógeno/farmacología , Unión Proteica , Estructura Terciaria de Proteína , Transfección
12.
Thromb Haemost ; 117(6): 1150-1163, 2017 06 02.
Artículo en Inglés | MEDLINE | ID: mdl-28447099

RESUMEN

We have recently identified endothelial cell-secreted developmental endothelial locus-1 (Del-1) as an endogenous inhibitor of ß2-integrin-dependent leukocyte infiltration. Del-1 was previously also implicated in angiogenesis. Here, we addressed the role of endogenously produced Del-1 in ischaemia-related angiogenesis. Intriguingly, Del-1-deficient mice displayed increased neovascularisation in two independent ischaemic models (retinopathy of prematurity and hind-limb ischaemia), as compared to Del-1-proficient mice. On the contrary, angiogenic sprouting in vitro or ex vivo (aortic ring assay) and physiological developmental retina angiogenesis were not affected by Del-1 deficiency. Mechanistically, the enhanced ischaemic neovascularisation in Del-1-deficiency was linked to higher infiltration of the ischaemic tissue by CD45+ haematopoietic and immune cells. Moreover, Del-1-deficiency promoted ß2-integrin-dependent adhesion of haematopoietic cells to endothelial cells in vitro, and the homing of hematopoietic progenitor cells and of immune cell populations to ischaemic muscles in vivo. Consistently, the increased hind limb ischaemia-related angiogenesis in Del-1 deficiency was completely reversed in mice lacking both Del-1 and the ß2-integrin LFA-1. Additionally, enhanced retinopathy-associated neovascularisation in Del-1-deficient mice was reversed by LFA-1 blockade. Our data reveal a hitherto unrecognised function of endogenous Del-1 as a local inhibitor of ischaemia-induced angiogenesis by restraining LFA-1-dependent homing of pro-angiogenic haematopoietic cells to ischaemic tissues. Our findings are relevant for the optimisation of therapeutic approaches in the context of ischaemic diseases.


Asunto(s)
Proteínas Portadoras/metabolismo , Endotelio Vascular/fisiología , Células Madre Hematopoyéticas/fisiología , Inflamación/metabolismo , Isquemia/metabolismo , Leucocitos/fisiología , Retinopatía de la Prematuridad/metabolismo , Animales , Proteínas de Unión al Calcio , Proteínas Portadoras/genética , Adhesión Celular , Moléculas de Adhesión Celular , Movimiento Celular , Modelos Animales de Enfermedad , Extremidades/patología , Células Endoteliales de la Vena Umbilical Humana , Humanos , Inflamación/inmunología , Péptidos y Proteínas de Señalización Intercelular , Isquemia/inmunología , Antígeno-1 Asociado a Función de Linfocito/genética , Antígeno-1 Asociado a Función de Linfocito/inmunología , Antígeno-1 Asociado a Función de Linfocito/metabolismo , Ratones , Ratones Noqueados , Neovascularización Fisiológica , ARN Interferente Pequeño/genética , Retinopatía de la Prematuridad/inmunología
13.
J Clin Invest ; 127(10): 3624-3639, 2017 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-28846069

RESUMEN

Hematopoietic stem cells (HSCs) remain mostly quiescent under steady-state conditions but switch to a proliferative state following hematopoietic stress, e.g., bone marrow (BM) injury, transplantation, or systemic infection and inflammation. The homeostatic balance between quiescence, self-renewal, and differentiation of HSCs is strongly dependent on their interactions with cells that constitute a specialized microanatomical environment in the BM known as the HSC niche. Here, we identified the secreted extracellular matrix protein Del-1 as a component and regulator of the HSC niche. Specifically, we found that Del-1 was expressed by several cellular components of the HSC niche, including arteriolar endothelial cells, CXCL12-abundant reticular (CAR) cells, and cells of the osteoblastic lineage. Del-1 promoted critical functions of the HSC niche, as it regulated long-term HSC (LT-HSC) proliferation and differentiation toward the myeloid lineage. Del-1 deficiency in mice resulted in reduced LT-HSC proliferation and infringed preferentially upon myelopoiesis under both steady-state and stressful conditions, such as hematopoietic cell transplantation and G-CSF- or inflammation-induced stress myelopoiesis. Del-1-induced HSC proliferation and myeloid lineage commitment were mediated by ß3 integrin on hematopoietic progenitors. This hitherto unknown Del-1 function in the HSC niche represents a juxtacrine homeostatic adaptation of the hematopoietic system in stress myelopoiesis.


Asunto(s)
Proteínas Portadoras/metabolismo , Células Madre Hematopoyéticas/metabolismo , Mielopoyesis , Nicho de Células Madre , Estrés Fisiológico , Animales , Proteínas de Unión al Calcio , Proteínas Portadoras/genética , Moléculas de Adhesión Celular , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Células Endoteliales/metabolismo , Humanos , Integrina beta3/genética , Integrina beta3/metabolismo , Péptidos y Proteínas de Señalización Intercelular , Ratones , Ratones Noqueados
14.
Mol Cell Biol ; 36(3): 376-93, 2016 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-26572826

RESUMEN

Angiogenesis is a central regulator for white (WAT) and brown (BAT) adipose tissue adaptation in the course of obesity. Here we show that deletion of hypoxia-inducible factor 2α (HIF2α) in adipocytes (by using Fabp4-Cre transgenic mice) but not in myeloid or endothelial cells negatively impacted WAT angiogenesis and promoted WAT inflammation, WAT dysfunction, hepatosteatosis, and systemic insulin resistance in obesity. Importantly, adipocyte HIF2α regulated vascular endothelial growth factor (VEGF) expression and angiogenesis of obese BAT as well as its thermogenic function. Consistently, obese adipocyte-specific HIF2α-deficient mice displayed BAT dysregulation, associated with reduced levels of uncoupling protein 1 (UCP1) and a dysfunctional thermogenic response to cold exposure. VEGF administration reversed WAT and BAT inflammation and BAT dysfunction in adipocyte HIF2α-deficient mice. Together, our findings show that adipocyte HIF2α is protective against maladaptation to obesity and metabolic dysregulation by promoting angiogenesis in both WAT and BAT and by counteracting obesity-mediated BAT dysfunction.


Asunto(s)
Adipocitos/patología , Tejido Adiposo Pardo/fisiopatología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Eliminación de Gen , Obesidad/genética , Obesidad/fisiopatología , Adipocitos/metabolismo , Tejido Adiposo Pardo/irrigación sanguínea , Tejido Adiposo Pardo/metabolismo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Inflamación/complicaciones , Canales Iónicos/metabolismo , Masculino , Ratones , Ratones Noqueados , Proteínas Mitocondriales/metabolismo , Neovascularización Fisiológica , Obesidad/complicaciones , Obesidad/metabolismo , Termogénesis , Proteína Desacopladora 1 , Factor A de Crecimiento Endotelial Vascular/metabolismo
15.
Arthritis Rheumatol ; 67(12): 3279-85, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26245636

RESUMEN

OBJECTIVE: Endothelial cell activation by tumor necrosis factor (TNF) and associated leukocyte infiltration are hallmarks of vasculitis. The aim of this study was to investigate the potential role of the cellular stress-associated endothelial X-box binding protein 1 (XBP-1) transcription factor in TNF-induced endothelial cell inflammation and vasculitis. METHODS: Mice with an endothelial cell-specific XBP-1 deficiency were used in a modified local Shwartzman reaction (LSR) model of TNF-induced small vessel vasculitis. To address the contribution of XBP-1 to the TNF-mediated inflammatory response in endothelial cells, we examined the activation of XBP-1 expression by TNF as well as the effect of XBP-1 knockdown in endothelial cells on TNF-induced signaling, proinflammatory gene expression, and leukocyte-endothelial cell adhesion. RESULTS: The active spliced form of XBP-1 in endothelial cells was triggered by TNF. In addition, endothelial XBP-1 contributed to the sustained TNF-triggered NF-κB-dependent transcriptional activation of proinflammatory molecules, which was associated with leukocyte-endothelial cell adhesion. In the LSR model, endothelial cell-specific XBP-1-deficient mice displayed significantly less vascular damage, accompanied by reduced perivascular neutrophil infiltration, as compared with wild-type mice. CONCLUSION: Endothelial XBP-1 is activated by TNF and regulates leukocyte-endothelial cell adhesion in vitro as well as neutrophil infiltration and vascular damage in murine vasculitis.


Asunto(s)
Adhesión Celular/genética , Proteínas de Unión al ADN/genética , Células Endoteliales/metabolismo , FN-kappa B/metabolismo , Infiltración Neutrófila/genética , Fenómeno de Shwartzman/genética , Factores de Transcripción/genética , Vasculitis/genética , Animales , Adhesión Celular/efectos de los fármacos , Adhesión Celular/inmunología , Proteínas de Unión al ADN/inmunología , Modelos Animales de Enfermedad , Células Endoteliales/efectos de los fármacos , Células Endoteliales/inmunología , Leucocitos/efectos de los fármacos , Leucocitos/inmunología , Leucocitos/metabolismo , Ratones , Ratones Noqueados , FN-kappa B/efectos de los fármacos , FN-kappa B/inmunología , Infiltración Neutrófila/efectos de los fármacos , Infiltración Neutrófila/inmunología , Factores de Transcripción del Factor Regulador X , Fenómeno de Shwartzman/inmunología , Factores de Transcripción/inmunología , Factor de Necrosis Tumoral alfa/farmacología , Vasculitis/inmunología , Proteína 1 de Unión a la X-Box
16.
Thromb Haemost ; 114(6): 1241-9, 2015 Nov 25.
Artículo en Inglés | MEDLINE | ID: mdl-26311310

RESUMEN

In proliferative retinopathies, like proliferative diabetic retinopathy and retinopathy of prematurity (ROP), the hypoxia response is sustained by the failure of the retina to revascularise its ischaemic areas. Non-resolving retina ischaemia/hypoxia results in upregulation of pro-angiogenic factors and pathologic neovascularisation with ectopic, fragile neovessels. Promoting revascularisation of the retinal avascular area could interfere with this vicious cycle and lead to vessel normalisation. Here, we examined the function of endothelial junctional adhesion molecule-C (JAM-C) in the context of ROP. Endothelial-specific JAM-C-deficient (EC-JAM-C KO) mice and littermate JAM-C-proficient (EC-JAM-C WT) mice were subjected to the ROP model. An increase in total retinal vascularisation was found at p17 owing to endothelial JAM-C deficiency, which was the result of enhanced revascularisation and vessel normalisation, thereby leading to significantly reduced avascular area in EC-JAM-C KO mice. In contrast, pathologic neovessel formation was not affected by endothelial JAM-C deficiency. Consistent with improved vessel normalisation, tip cell formation at the interface between vascular and avascular area was higher in EC-JAM-C KO mice, as compared to their littermate controls. Consistently, JAM-C inactivation in endothelial cells resulted in increased spreading on fibronectin and enhanced sprouting in vitro in a manner dependent on ß1-integrin and on the activation of the small GTPase RAP1. Together, endothelial deletion of JAM-C promoted endothelial cell sprouting, and consequently vessel normalisation and revascularisation of the hypoxic retina without altering pathologic neovascularisation. Thus, targeting endothelial JAM-C may provide a novel therapeutic strategy for promoting revascularisation and vessel normalisation in the treatment of proliferative retinopathies.


Asunto(s)
Endotelio Vascular/fisiopatología , Molécula C de Adhesión de Unión/deficiencia , Neovascularización Patológica/fisiopatología , Vasos Retinianos/fisiopatología , Retinopatía de la Prematuridad/fisiopatología , Vitreorretinopatía Proliferativa/fisiopatología , Animales , Adhesión Celular , Hipoxia de la Célula , Línea Celular , Tamaño de la Célula , Extensiones de la Superficie Celular , Modelos Animales de Enfermedad , Células Endoteliales , Endotelio Vascular/patología , Fibronectinas , Células Endoteliales de la Vena Umbilical Humana , Humanos , Integrina beta1/fisiología , Isquemia/fisiopatología , Molécula C de Adhesión de Unión/fisiología , Ratones , Ratones Noqueados , Neovascularización Patológica/etiología , Especificidad de Órganos , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/análisis , Interferencia de ARN , ARN Interferente Pequeño/genética , Vasos Retinianos/ultraestructura , Proteínas de Unión al GTP rap1/fisiología
17.
Int J Radiat Biol ; 90(8): 700-9, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24512568

RESUMEN

PURPOSE: In this work we examined the presence of the neural stem cell biomarker Hairy and Enhancer of Split 3 (Hes3) in the anterior eye segment and in the aberrant growth condition of the conjunctiva pterygium. Further, we studied the response of Hes3 to irradiation. MATERIALS AND METHODS: Adult mouse and human corneoscleral junction and conjunctiva, as well as human pterygium were prepared for immunohistochemical detection of Hes3 and other markers. Total body irradiation was used to study the changes in the pattern of Hes3 expression. RESULTS: The adult rodent and human eye as well as pterygium, contain a population of cells expressing Hes3. In the human eye, Hes3-expressing (Hes3+) cells are found predominantly in the subconjunctival space spanning over the limbus where they physically associate with blood vessels. The cytoarchitecture of Hes3 + cells is similar to those previously observed in the adult central nervous system. Furthermore, irradiation reduces the number of Hes3 + cells in the subconjunctival space. In contrast, irradiation strongly promotes the nuclear localization of Hes3 in the ciliary body epithelium. CONCLUSIONS: Our results suggest that a recently identified signal transduction pathway that regulates neural stem cells and glioblastoma cancer stem cells also operates in the ocular surface, ciliary body, and in pterygium.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Proteínas de Unión al ADN/metabolismo , Ojo/metabolismo , Regulación de la Expresión Génica , Proteínas del Tejido Nervioso/metabolismo , Pterigion/metabolismo , Factores de Transcripción/metabolismo , Animales , Conjuntiva/efectos de los fármacos , Conjuntiva/metabolismo , Conjuntiva/efectos de la radiación , Ojo/irrigación sanguínea , Ojo/efectos de los fármacos , Ojo/efectos de la radiación , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/efectos de la radiación , Humanos , Ratones , Terapia Molecular Dirigida , Neovascularización Fisiológica/efectos de los fármacos , Neovascularización Fisiológica/efectos de la radiación , Pterigion/tratamiento farmacológico , Pterigion/fisiopatología , Proteínas Represoras
20.
Invest Ophthalmol Vis Sci ; 50(3): 1454-63, 2009 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-19060272

RESUMEN

PURPOSE: To determine the localization of JAM-C in human RPE and characterize its functions. METHODS: Immunofluorescence, Western blot, and PCR was used to identify the localization and expression of JAM-C, ZO-1, N-cadherin, and ezrin in cultures of human fetal RPE (hfRPE) with or without si-RNA mediated JAM-C knockdown and in adult native RPE wholemounts. A transepithelial migration assay was used to study the migration of leukocytes through the hfRPE monolayer. RESULTS: JAM-C localized at the tight junctions of cultured hfRPE cells and adult native RPE. During initial junction formation JAM-C was recruited to the primordial cell-cell contacts and after JAM-C knockdown, the organization of N-cadherin and ZO-1 at those contacts was disrupted. JAM-C knockdown caused a delay in the hfRPE cell polarization, as shown by reduced apical staining of ezrin. JAM-C inhibition significantly decreased the chemokine-induced transmigration of granulocytes but not monocytes through the hfRPE monolayer. CONCLUSIONS: JAM-C localizes specifically in the tight junctions of hfRPE and adult native RPE. It is important for tight junction formation in hfRPE, possibly by regulating the recruitment of N-cadherin and ZO-1 at the cell-cell contacts, and has a role in the polarization of hfRPE cells. Finally, JAM-C promotes the basal-to-apical transmigration of granulocytes but not monocytes through the hfRPE monolayer.


Asunto(s)
Moléculas de Adhesión Celular/metabolismo , Epitelio Pigmentado de la Retina/metabolismo , Antígenos CD/metabolismo , Western Blotting , Cadherinas/metabolismo , Ensayos de Migración de Leucocitos , Polaridad Celular , Células Cultivadas , Citocinas/farmacología , Proteínas del Citoesqueleto/metabolismo , Técnica del Anticuerpo Fluorescente Indirecta , Granulocitos/fisiología , Humanos , Proteínas de la Membrana/metabolismo , Monocitos/fisiología , Fosfoproteínas/metabolismo , Reacción en Cadena de la Polimerasa , ARN Interferente Pequeño/farmacología , Epitelio Pigmentado de la Retina/embriología , Uniones Estrechas/metabolismo , Proteína de la Zonula Occludens-1
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