RESUMEN

Background: Refractory angina (RFA; limiting angina despite optimal medical therapy) is a growing, global problem, with limited treatment options. Therefore, we conducted a systematic review of randomized controlled trials (RCTs) to evaluate the effect of proangiogenic growth factor therapy (in the form of vascular growth factors delivered either as recombinant proteins or gene therapy) in patients with RFA ineligible for revascularization. Methods: We performed a meta-analysis (PROSPERO: CRD42018107283) of RCTs as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology. A comprehensive search of the PubMed, CENTRAL, Embase, Cochrane, ClinicalTrials.gov and Google Scholar databases, as well as scientific session abstracts, were performed. The pooled outcomes included major adverse cardiac events (MACE), mortality, myocardial perfusion, and indices of angina severity (Canadian Cardiovascular Society angina class [CCS] and exercise tolerance). A prespecified subgroup analysis was performed for delivery method, vector, and protein type. The standardized mean difference (SMD) or odds ratio (OR) was calculated to assess relevant outcomes. We assessed heterogeneity using the χ2 and I2 tests. Results: We included 16 RCTs involving 1607 patients (1052 received proangiogenic growth factor therapy and 555 received a placebo or optimal medical therapy). Our analysis showed a significant decreased risk of MACE (OR, 0.72; 95% confidence interval [CI], 0.55-0.93) and significantly improved CCS class (SMD, -0.55; 95% CI, -1.10 to 0.00), but not mortality (OR, 0.66; 95% CI, 0.28-1.54) or exercise tolerance (SMD, 0.47; 95% CI, -0.14 to 1.09), in treated patients compared to those in the control group. Conclusions: Proangiogenic growth factor therapy is a promising treatment option for RFA, with beneficial effects seen on MACE and CCS class. The results of ongoing trials are needed before it can be considered for clinical practice.

RESUMEN

The heparan sulphate proteoglycan Syndecan-4 belongs to a 4-member family of transmembrane receptors. Genetic deletion of Syndecan-4 in mice causes negligible developmental abnormalities however when challenged these animals show distinct phenotypes. Synedcan-4 is expressed in many cell types in the heart and its expression is elevated in response to cardiac injury and recent studies have suggested roles for Syndecan-4 in repair mechanisms within the damaged heart. The purpose of this review is to explore these biological insights into the role of Syndecan-4 in both the injured heart and later during cardiac repair and remodeling.

Asunto(s)

Corazón , Sindecano-4 , Animales , Ratones , Sindecano-4/genética

RESUMEN

The syndecans are the major family of transmembrane proteoglycans, usually bearing multiple heparan sulfate chains. They are present on virtually all nucleated cells of vertebrates and are also present in invertebrates, indicative of a long evolutionary history. Genetic models in both vertebrates and invertebrates have shown that syndecans link to the actin cytoskeleton and can fine-tune cell adhesion, migration, junction formation, polarity and differentiation. Although often associated as co-receptors with other classes of receptors (e.g. integrins, growth factor and morphogen receptors), syndecans can nonetheless signal to the cytoplasm in discrete ways. Syndecan expression levels are upregulated in development, tissue repair and an array of human diseases, which has led to the increased appreciation that they may be important in pathogenesis not only as diagnostic or prognostic agents, but also as potential targets. Here, their functions in development and inflammatory diseases are summarized, including their potential roles as conduits for viral pathogen entry into cells.

Asunto(s)

Sindecanos/metabolismo , Animales , Regulación del Desarrollo de la Expresión Génica , Heparitina Sulfato/metabolismo , Humanos , Enfermedades del Sistema Inmune/metabolismo , Transducción de Señal , Sindecanos/química

RESUMEN

[Figure: see text].

Asunto(s)

Antígenos CD/metabolismo , Cadherinas/metabolismo , Neovascularización Coroidal/metabolismo , Degeneración Macular/metabolismo , Melanoma Experimental/metabolismo , Neovascularización Patológica , Neovascularización Fisiológica/efectos de los fármacos , Neovascularización Retiniana/metabolismo , Vasos Retinianos/efectos de los fármacos , Vasos Retinianos/metabolismo , Vasos Retinianos/patología , Neoplasias Cutáneas/metabolismo , Sindecano-4/metabolismo , Factor A de Crecimiento Endotelial Vascular/farmacología , Animales , Permeabilidad Capilar , Neovascularización Coroidal/genética , Neovascularización Coroidal/patología , Modelos Animales de Enfermedad , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Femenino , Humanos , Degeneración Macular/genética , Degeneración Macular/patología , Masculino , Melanoma Experimental/genética , Melanoma Experimental/patología , Ratones Endogámicos C57BL , Ratones Noqueados , Neovascularización Retiniana/genética , Neovascularización Retiniana/patología , Transducción de Señal , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Sindecano-4/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/agonistas , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo

RESUMEN

Osteoarthritis is characterized by the loss of the articular cartilage, bone remodeling, pain, and disability. No pharmacological intervention can currently halt progression of osteoarthritis. Here, we show that blocking receptor tyrosine kinase-like orphan receptor 2 (ROR2) improves cartilage integrity and pain in osteoarthritis models by inhibiting yes-associated protein (YAP) signaling. ROR2 was up-regulated in the cartilage in response to inflammatory cytokines and mechanical stress. The main ligand for ROR2, WNT5A, and the targets YAP and connective tissue growth factor were up-regulated in osteoarthritis in humans. In vitro, ROR2 overexpression inhibited chondrocytic differentiation. Conversely, ROR2 blockade triggered chondrogenic differentiation of C3H10T1/2 cells and suppressed the expression of the cartilage-degrading enzymes a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4 and ADAMTS-5. The chondrogenic effect of ROR2 blockade in the cartilage was independent of WNT signaling and was mediated by down-regulation of YAP signaling. ROR2 signaling induced G protein and Rho-dependent nuclear accumulation of YAP, and YAP inhibition was required but not sufficient for ROR2 blockade-induced chondrogenesis. ROR2 silencing protected mice from instability-induced osteoarthritis with improved structural outcomes, sustained pain relief, and without apparent side effects or organ toxicity. Last, ROR2 silencing in human articular chondrocytes transplanted in nude mice led to the formation of cartilage organoids with more and better differentiated extracellular matrix, suggesting that the anabolic effect of ROR2 blockade is conserved in humans. Thus, ROR2 blockade is efficacious and well tolerated in preclinical animal models of osteoarthritis.

Asunto(s)

Condrogénesis , Osteoartritis , Animales , Diferenciación Celular , Condrocitos , Ratones , Ratones Desnudos , Osteoartritis/tratamiento farmacológico , Receptores Huérfanos Similares al Receptor Tirosina Quinasa

RESUMEN

Cartilage loss leads to osteoarthritis, the most common cause of disability for which there is no cure. Cartilage regeneration, therefore, is a priority in medicine. We report that agrin is a potent chondrogenic factor and that a single intraarticular administration of agrin induced long-lasting regeneration of critical-size osteochondral defects in mice, with restoration of tissue architecture and bone-cartilage interface. Agrin attracted joint resident progenitor cells to the site of injury and, through simultaneous activation of CREB and suppression of canonical WNT signaling downstream of ß-catenin, induced expression of the chondrogenic stem cell marker GDF5 and differentiation into stable articular chondrocytes, forming stable articular cartilage. In sheep, an agrin-containing collagen gel resulted in long-lasting regeneration of bone and cartilage, which promoted increased ambulatory activity. Our findings support the therapeutic use of agrin for joint surface regeneration.

Asunto(s)

Agrina , Cartílago Articular , Animales , Diferenciación Celular , Condrocitos , Condrogénesis , Ratones , Ovinos , Andamios del Tejido

RESUMEN

Syndecans are a four member multifunctional family of cell surface molecules with diverse biological roles. Syndecan-3 (SDC3) is the largest of these, but in comparison to the other family members relatively little is known about this molecule. SDC3 null mice grow and develop normally, all be it with subtle anatomical phenotypes in the brain. Roles for this molecule in both neuronal and brain tissue have been identified, and is associated with altered satiety responses. Recent studies suggest that SDC3 expression is not restricted to neuronal tissues and has important roles in inflammatory disorders such as rheumatoid arthritis, disease associated processes such as angiogenesis and in the facilitation of infection of dendritic cells by HIV. The purpose of this review article is to explore these new biological insights into SDC3 functions in inflammatory disease.

Asunto(s)

Inflamación/inmunología , Neovascularización Patológica/inmunología , Sindecano-3/inmunología , Animales , Humanos

RESUMEN

LINKED ARTICLES: This article is part of a themed section on Translating the Matrix. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.1/issuetoc.

Asunto(s)

Matriz Extracelular/metabolismo , Animales , Humanos

RESUMEN

Chronically inflamed tissues show altered characteristics that include persistent populations of inflammatory leukocytes and remodelling of the vascular network. As the majority of studies on leukocyte recruitment have been carried out in normal healthy tissues, the impact of underlying chronic inflammation on ongoing leukocyte recruitment is largely unknown. Here, we investigate the profile and mechanisms of acute inflammatory responses in chronically inflamed and angiogenic tissues, and consider the implications for chronic inflammatory disorders. We have developed a novel model of chronic ischaemia of the mouse cremaster muscle that is characterized by a persistent population of monocyte-derived cells (MDCs), and capillary angiogenesis. These tissues also show elevated acute neutrophil recruitment in response to locally administered inflammatory stimuli. We determined that Gr1low MDCs, which are widely considered to have anti-inflammatory and reparative functions, amplified acute inflammatory reactions via the generation of additional proinflammatory signals, changing both the profile and magnitude of the tissue response. Similar vascular and inflammatory responses, including activation of MDCs by transient ischaemia-reperfusion, were observed in mouse hindlimbs subjected to chronic ischaemia. This response demonstrates the relevance of the findings to peripheral arterial disease, in which patients experience transient exercise-induced ischaemia known as claudication.These findings demonstrate that chronically inflamed tissues show an altered profile and altered mechanisms of acute inflammatory responses, and identify tissue-resident MDCs as potential therapeutic targets. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Asunto(s)

Músculos Abdominales/irrigación sanguínea , Inflamación/etiología , Claudicación Intermitente/etiología , Isquemia/complicaciones , Neovascularización Patológica/etiología , Infiltración Neutrófila/inmunología , Músculos Abdominales/inmunología , Músculos Abdominales/patología , Enfermedad Aguda , Animales , Enfermedad Crónica , Modelos Animales de Enfermedad , Genes Reporteros , Miembro Posterior/irrigación sanguínea , Miembro Posterior/patología , Humanos , Inflamación/inmunología , Inflamación/fisiopatología , Claudicación Intermitente/fisiopatología , Isquemia/inmunología , Isquemia/fisiopatología , Leucocitos/inmunología , Macrófagos/inmunología , Ratones , Ratones Endogámicos C57BL , Monocitos/inmunología , Neovascularización Patológica/fisiopatología , Neutrófilos/inmunología

RESUMEN

The potential of induced pluripotent stem cells (iPSCs) in disease modeling and regenerative medicine is vast, but current methodologies remain inefficient. Understanding the cellular mechanisms underlying iPSC reprogramming, such as the metabolic shift from oxidative to glycolytic energy production, is key to improving its efficiency. We have developed a lentiviral reporter system to assay longitudinal changes in cell signaling and transcription factor activity in living cells throughout iPSC reprogramming of human dermal fibroblasts. We reveal early NF-κB, AP-1, and NRF2 transcription factor activation prior to a temporal peak in hypoxia inducible factor α (HIFα) activity. Mechanistically, we show that an early burst in oxidative phosphorylation and elevated reactive oxygen species generation mediates increased NRF2 activity, which in turn initiates the HIFα-mediated glycolytic shift and may modulate glucose redistribution to the pentose phosphate pathway. Critically, inhibition of NRF2 by KEAP1 overexpression compromises metabolic reprogramming and results in reduced efficiency of iPSC colony formation.

Asunto(s)

Reprogramación Celular , Fibroblastos/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/genética , Factor 2 Relacionado con NF-E2/genética , Dermis/citología , Dermis/metabolismo , Fibroblastos/citología , Regulación de la Expresión Génica , Genes Reporteros , Vectores Genéticos/química , Vectores Genéticos/metabolismo , Glucólisis/genética , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Células Madre Pluripotentes Inducidas/citología , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Lentivirus/genética , Lentivirus/metabolismo , Luciferasas/genética , Luciferasas/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/genética , FN-kappa B/metabolismo , Fosforilación Oxidativa , Vía de Pentosa Fosfato/genética , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Factor de Transcripción AP-1/genética , Factor de Transcripción AP-1/metabolismo , Transducción Genética

RESUMEN

Intracellular adhesion molecule-1 (ICAM-1) is a transmembrane glycoprotein expressed on the cell surface of numerous cell types such as endothelial and epithelial cells, vascular smooth muscle cells, and certain leukocyte subsets. With respect to the latter, ICAM-1 has been detected on neutrophils in several clinical and experimental settings, but little is known about the regulation of expression or function of neutrophil ICAM-1. In this study, we report on the de novo induction of ICAM-1 on the cell surface of murine neutrophils by lipopolysaccharide (LPS), tumor necrosis factor, and zymosan particles in vitro. The induction of neutrophil ICAM-1 was associated with enhanced phagocytosis of zymosan particles and reactive oxygen species (ROS) generation. Conversely, neutrophils from ICAM-1-deficient mice were defective in these effector functions. Mechanistically, ICAM-1-mediated intracellular signaling appeared to support neutrophil ROS generation and phagocytosis. In vivo, LPS-induced inflammation in the mouse cremaster muscle and peritoneal cavity led to ICAM-1 expression on intravascular and locally transmigrated neutrophils. The use of chimeric mice deficient in ICAM-1 on myeloid cells demonstrated that neutrophil ICAM-1 was not required for local neutrophil transmigration, but supported optimal intravascular and extravascular phagocytosis of zymosan particles. Collectively, the present results shed light on regulation of expression and function of ICAM-1 on neutrophils and identify it as an additional regulator of neutrophil effector responses in host defense.

Asunto(s)

Endotoxemia/inducido químicamente , Endotoxemia/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Molécula 1 de Adhesión Intercelular/biosíntesis , Lipopolisacáridos/toxicidad , Neutrófilos/metabolismo , Animales , Modelos Animales de Enfermedad , Endotoxemia/genética , Endotoxemia/patología , Molécula 1 de Adhesión Intercelular/genética , Ratones , Ratones Noqueados , Neutrófilos/patología , Fagocitosis/efectos de los fármacos , Fagocitosis/genética , Especies Reactivas de Oxígeno/metabolismo , Migración Transendotelial y Transepitelial/efectos de los fármacos , Migración Transendotelial y Transepitelial/genética

RESUMEN

Sexual dimorphisms exist in the incidence and severity of many diseases, with females demonstrating relative protection from inflammatory conditions. The extent and mechanisms by which excessive leukocyte recruitment underlies these differences are not well established, and better understanding is essential for the development of targeted therapies. Here, we set out to compare the male and female inflammatory response in a murine zymosan-induced peritonitis model and to understand how leukocyte subsets are mobilized from storage pools in both sexes. This work shows that female C57BL/6 mice recruit fewer classical monocytes and neutrophils during zymosan-induced peritonitis. In addition, sex differences were evident in the circulation, as female mice showed reduced neutrophilia and monocytosis vs. male counterparts, despite having similar mobilization from BM stores. Importantly, we show that storage and trafficking of splenic leukocytes during acute inflammation are distinct between the sexes. Male mice have greater splenic stores of neutrophils and classical and nonclassical monocytes, despite similar spleen sizes, signifying another source of potential pathogenic leukocytes. This work demonstrates that males and females have distinct leukocyte-trafficking profiles in acute inflammation and suggests that the spleen, not the BM, plays a role in determining sex differences in the available pool of immune cells. Such dimorphisms demonstrate the importance of considering gender in assay development, drug design, and clinical trials.

Asunto(s)

Médula Ósea/inmunología , Movimiento Celular/inmunología , Monocitos/inmunología , Neutrófilos/inmunología , Caracteres Sexuales , Animales , Femenino , Inflamación , Masculino , Ratones

RESUMEN

The cytokine IL6 has a number of tumor-promoting activities in human and experimental cancers, but its potential as an angiogenic agent has not been fully investigated. Here, we show that IL6 can directly induce vessel sprouting in the ex vivo aortic ring model, as well as endothelial cell proliferation and migration, with similar potency to VEGF. However, IL6-stimulated aortic ring vessel sprouts had defective pericyte coverage compared with VEGF-stimulated vessels. The mechanism of IL6 action on pericytes involved stimulation of the Notch ligand Jagged1 as well as angiopoietin2 (Ang2). When peritoneal xenografts of ovarian cancer were treated with an anti-IL6 antibody, pericyte coverage of vessels was restored. In addition, in human ovarian cancer biopsies, there was an association between levels of IL6 mRNA, Jagged1, and Ang2. Our findings have implications for the use of cancer therapies that target VEGF or IL6 and for understanding abnormal angiogenesis in cancers, chronic inflammatory disease, and stroke.

Asunto(s)

Interleucina-6/metabolismo , Interleucina-6/farmacología , Neovascularización Patológica/metabolismo , Animales , Aorta/efectos de los fármacos , Aorta/patología , Proteínas de Unión al Calcio/genética , Línea Celular Tumoral , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Células Endoteliales/patología , Femenino , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Interleucina-6/genética , Proteína Jagged-1 , Masculino , Proteínas de la Membrana/genética , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Terapia Molecular Dirigida/métodos , Neovascularización Patológica/inducido químicamente , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/patología , Técnicas de Cultivo de Órganos , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Pericitos/efectos de los fármacos , Pericitos/patología , Ratas Wistar , Proteínas Serrate-Jagged , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/farmacología , Proteínas de Transporte Vesicular/genética , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

Syndecans are multifunctional heparan sulfate proteoglycans (HSPGs) with roles in cell adhesion, migration, receptor trafficking and growth-factor interactions and signalling. Studies using syndecan null animals have revealed limited roles for syndecans during development; however, under conditions of challenge or insult, several phenotypes have emerged. Angiogenesis is an important process both in development and in wound healing, but also in pathologies such as cancer and chronic inflammatory conditions. In the present paper, we summarize the main studies elucidating the role of syndecans in angiogenesis and their potential as novel therapeutic targets.

Asunto(s)

Endotelio Vascular/metabolismo , Neovascularización Patológica , Neovascularización Fisiológica/fisiología , Sindecanos/fisiología , Endotelio Vascular/citología , Humanos

RESUMEN

Angiogenesis is essential for the development of a normal vasculature, tissue repair and reproduction, and also has roles in the progression of diseases such as cancer and rheumatoid arthritis. The heparan sulphate proteoglycan syndecan-2 is expressed on mesenchymal cells in the vasculature and, like the other members of its family, can be shed from the cell surface resulting in the release of its extracellular core protein. The purpose of this study was to establish whether shed syndecan-2 affects angiogenesis. We demonstrate that shed syndecan-2 regulates angiogenesis by inhibiting endothelial cell migration in human and rodent models and, as a result, reduces tumour growth. Furthermore, our findings show that these effects are mediated by the protein tyrosine phosphatase receptor CD148 (also known as PTPRJ) and this interaction corresponds with a decrease in active ß1 integrin. Collectively, these data demonstrate an unexplored pathway for the regulation of new blood vessel formation and identify syndecan-2 as a therapeutic target in pathologies characterised by angiogenesis.

Asunto(s)

Neovascularización Patológica/metabolismo , Sindecano-2/metabolismo , Animales , Movimiento Celular/genética , Movimiento Celular/fisiología , Células Cultivadas , Células Endoteliales/metabolismo , Humanos , Ratones , Ratones SCID , Sindecano-2/genética , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

Inflammation is an essential process in response to injury and infection. However, under certain circumstances dis-regulation of this process can lead to pathologies such as rheumatoid arthritis, atherosclerosis, lupus, and is a contributory factor in the progression of many cancers. The Toll-like family of receptors (TLRs) has major roles in the initiation of the inflammatory response and as such has attracted much focus for their potential as therapeutic targets. Here we review the role of TLRs in the inflammatory response and associated disease and examine how this important family of molecules might be targeted for therapeutic benefit.

Asunto(s)

Receptores Toll-Like/fisiología , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Médula Ósea/inmunología , Médula Ósea/patología , Interacciones Huésped-Patógeno , Humanos , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Inflamación/metabolismo , Mediadores de Inflamación/fisiología , Monocitos/inmunología , Monocitos/metabolismo , Transducción de Señal , Receptores Toll-Like/antagonistas & inhibidores

RESUMEN

Junctional adhesion molecule C (JAM-C) is a transmembrane protein with significant roles in regulation of endothelial cell (EC) functions, including immune cell recruitment and angiogenesis. As these responses are important in promoting tumor growth, the role of EC JAM-C in tumor development was investigated using the ID8 syngeneic model of ovarian cancer. Within 10-15 wk, intraperitoneally injected ID8 cells form multiple tumor deposits and ascites that resemble human high-grade serous ovarian cancer. Compared to wild-type mice, survival in this model was increased in EC JAM-C knockouts (KOs; 88 vs. 96 d, P=0.04) and reduced in EC JAM-C transgenics (88 vs. 78.5 d, P=0.03), mice deficient in or overexpressing EC JAM-C, respectively. While tumor growth was significantly reduced in EC JAM-C KOs (87% inhibition at 10 wk, P<0.0005), this was not associated with alterations in tumor vessel density or immune cell infiltration. However, tumor microvessels from EC JAM-C-deficient mice exhibited reduced pericyte coverage and increased vascular leakage, suggesting a role for EC JAM-C in the development of functional tumor vessels. These findings provide evidence for a role for EC JAM-C in tumor growth and aggressiveness as well as recruitment of pericytes to newly formed blood vessels in a model of ovarian cancer.

Asunto(s)

Moléculas de Adhesión Celular/metabolismo , Regulación Neoplásica de la Expresión Génica/fisiología , Inmunoglobulinas/metabolismo , Neoplasias Ováricas/metabolismo , Animales , Moléculas de Adhesión Celular/genética , Línea Celular Tumoral , Femenino , Regulación de la Expresión Génica/fisiología , Humanos , Inmunoglobulinas/genética , Ratones , Ratones Noqueados , Neoplasias Experimentales/genética , Neoplasias Experimentales/metabolismo , Neovascularización Patológica , Neoplasias Ováricas/irrigación sanguínea

RESUMEN

Syndecans are a four member family of multifunctional transmembrane heparan sulphate bearing cell surface receptors. Each family member has common molecular architecture but a distinct expression profile. Numerous molecular interactions between syndecan heparan sulphate chains, growth factors, cytokines, and extracellular matrix molecules have been reported and syndecans are intimately associated with cell adhesion and migration. Here, we describe the important emerging concept that contained within syndecan extracellular core proteins are "adhesion regulatory domains." Cell adhesion is driven by the integrins and syndecan ectodomain adhesion regulatory domains can alter integrin driven cellular responses. Cell adhesion and migration is central to numerous pathologies and an understanding of how syndecan ectodomains influence integrins will lead to novel therapeutic strategies.

Asunto(s)

Sindecanos/fisiología , Animales , Desarrollo Embrionario , Matriz Extracelular/fisiología , Humanos , Estructura Terciaria de Proteína/fisiología , Transducción de Señal , Sindecanos/química

RESUMEN

Syndecan-3 is one of the four members of the syndecan family of heparan sulphate proteoglycans and has been shown to interact with numerous growth factors via its heparan sulphate chains. The extracellular core proteins of syndecan-1,-2 and -4 all possess adhesion regulatory motifs and we hypothesized that syndecan-3 may also possess such characteristics. Here we show that a bacterially expressed GST fusion protein consisting of the entire mature syndecan-3 ectodomain has anti-angiogenic properties and acts via modulating endothelial cell migration. This work identifies syndecan-3 as a possible therapeutic target for anti-angiogenic therapy.

RESUMEN

Syndecan-2 is a heparan sulfate proteoglycan that has a cell adhesion regulatory domain contained within its extracellular core protein. Cell adhesion to the syndecan-2 extracellular domain (S2ED) is ß1 integrin dependent; however, syndecan-2 is not an integrin ligand. Here the protein tyrosine phosphatase receptor CD148 is shown to be a key intermediary in cell adhesion to S2ED, with downstream ß1 integrin-mediated adhesion and cytoskeletal organization. We show that S2ED is a novel ligand for CD148 and identify the region proximal to the transmembrane domain of syndecan-2 as the site of interaction with CD148. A mechanism for the transduction of the signal from CD148 to ß1 integrins is elucidated requiring Src kinase and potential implication of the C2ß isoform of phosphatidylinositol 3 kinase. Our data uncover a novel pathway for ß1 integrin-mediated adhesion of importance in cellular processes such as angiogenesis and inflammation.

Asunto(s)

Citoesqueleto/metabolismo , Integrina beta1/metabolismo , Sindecano-2/metabolismo , Animales , Adhesión Celular , Línea Celular , Citoesqueleto/genética , Fibroblastos/citología , Regulación de la Expresión Génica , Humanos , Inflamación/genética , Inflamación/metabolismo , Integrina beta1/genética , Células Jurkat , Ligandos , Pulmón/citología , Ratones , Neovascularización Fisiológica/genética , Fosfatidilinositol 3-Quinasa/metabolismo , Dominios y Motivos de Interacción de Proteínas/genética , ARN Interferente Pequeño , Ratas , Proteínas Tirosina Fosfatasas Clase 3 Similares a Receptores/genética , Proteínas Tirosina Fosfatasas Clase 3 Similares a Receptores/metabolismo , Transducción de Señal , Sindecano-2/genética , Familia-src Quinasas/metabolismo