1,721,297 research outputs found
Endothelial cell dysfunction in globoid cell leukodystrophy
No full textAngiogenesis plays a pivotal role in the physiology and pathology of the brain. Microvascular alterations have been observed in various neurodegenerative disorders, including genetic leukodystrophies. Globoid cell leukodystrophy (GLD) is a lysosomal storage disease caused by β-galactosylceramidase (GALC) deficiency and characterized by the accumulation of the neurotoxic metabolite psychosine in the central nervous system and peripheral tissues. Structural and functional alterations occur in the microvascular endothelium of the brain of GLD patients and twitcher mice, a murine model of the disease. In addition, increased vessel permeability and a reduced capacity to respond to proangiogenic stimuli characterize the endothelium of twitcher animals. On the one hand, these alterations may depend, at least in part, on the local and systemic angiostatic activity exerted by psychosine on endothelial cells. On the other hand, studies performed in vivo on zebrafish embryos and in vitro on human endothelial cells suggest that GALC downregulation may also lead to psychosine-independent neuronal and vascular defects. Together, experimental observations indicate that endothelial cell dysfunctions may represent a novel pathogenic mechanism in human leukodystrophies, including GLD. A better understanding of the molecular mechanisms responsible for these microvascular alterations may provide new insights for the therapy of GLD. © 2016 Wiley Periodicals, Inc
HIV-1 Tat protein and endothelium, from protein-cell interaction to AIDS associated pathologies
No full textInteraction of angiogenic basic fibroblast growth factor with endothelial cell heparan sulfate proteoglycans: biological implications in neovascularization
No full textBasic fibroblast growth factor is an angiogenic molecule involved in several physiological and pathological processes, including wound repair, embryonic development, and tumor growth. In vitro, basic fibroblast growth factor induces an "angiogenic phenotype" in endothelial cells, which includes chemotaxis, mitogenesis, protease production, beta-integrin expression, and tube formation in three-dimensional gels. It acts by binding to specific tyrosine kinase receptors and to cell-associated heparan sulfate proteoglycans. The physiological significance of the interaction with cell-associated and soluble heparan sulfate proteoglycans is manyfold. Heparan sulfate proteoglycans protect basic fibroblast growth factor from inactivation in the extracellular environment and modulate its bioavailability. At the cell surface, soluble and cell-associated heparan sulfate proteoglycans may play different roles in modulating the dimerization of the growth factor and its interaction with tyrosine kinase receptors. Finally, they affect the internalization and the intracellular fate of basic fibroblast growth factor, suggesting that growth factor slash proteoglycan complexes are involved in intracellular delivery. The bioavailability and the biological activity of basic fibroblast growth factor on endothelial cells strictly depend on the glycosaminoglycan milieu of the extracellular environment. Hence the angiogenic activity of the growth factor in vivo might be modulated by using exogenous glycosaminoglycans. The capacity of glycosaminoglycans to bind to and to influence the biological activity of basic fibroblast growth factor depends on size, degree of sulfation, and disaccharide composition. In the present paper we discuss the physiological significance and the biochemical bases of the interaction of the growth factor with heparan sulfate proteoglycans and exogenous glycosaminoglycans with a view to the possible therapeutic use of heparin-related oligosaccharides as basic fibroblast growth factor agonists or antagonists in angiogenesis-dependent diseases
Angiogenic growth factors interactome and drug discovery: The contribution of surface plasmon resonance
No full textAngiogenesis is implicated in several pathological conditions, including cancer, and in regenerative processes, including the formation of collateral blood vessels after stroke. Physiological angiogenesis is the outcome of a fine balance between the action of angiogenic growth factors (AGFs) and anti-angiogenic molecules, while pathological angiogenesis occurs when this balance is pushed toward AGFs. AGFs interact with multiple endothelial cell (EC) surface receptors inducing cell proliferation, migration and proteases upregulation. On the contrary, free or extracellular matrix-associated molecules inhibit angiogenesis by sequestering AGFs (thus hampering EC stimulation) or by interacting with specific EC receptors inducing apoptosis or decreasing responsiveness to AGFs. Thus, angiogenesis results from an intricate network of interactions among pro- and anti-angiogenic molecules, EC receptors and various modulators. All these interactions represent targets for the development of pro- or anti-angiogenic therapies. These aims call for suitable technologies to study the countless interactions occurring during neovascularization. Surface plasmon resonance (SPR) is a label-free optical technique to study biomolecular interactions in real time. It has become the golden standard technology for interaction analysis in biomedical research, including angiogenesis. From a survey of the literature it emerges that SPR has already contributed substantially to the better understanding of the neovascularization process, laying the basis for the decoding of the angiogenesis "interactome" and the identification of "hub molecules" that may represent preferential targets for an efficacious modulation of angiogenesis. Here, the still unexploited full potential of SPR is enlightened, pointing to improvements in its use for a deeper understanding of the mechanisms of neovascularization and the identification of novel anti-angiogenic drugs
Extracellular angiogenic growth factor interactions: an angiogenesis interactome survey
No full textAngiogenesis plays a key role in various physiological and pathological processes, including inflammation and tumor growth. Numerous angiogenic growth factors (AGFs) have been identified. Usually, the angiogenic process is assumed to represent the outcome of a straightforward interaction of AGFs with specific signalling receptors of the endothelial cell (EC) surface. Actually, the mechanisms by which AGFs induce neovascularization are much more complex. Indeed, angiogenesis is the result of the simultaneous actions of various AGFs and angiogenesis modulators; multiple EC surface receptors with different structure and biological properties are engaged by AGFs to exert a full angiogenic response; AGFs bind a variety of free and immobilized proteins, polysaccharides, and complex lipids of the extracellular milieu that affect AGF integrity, stability, and bioavailability; some of the AGF-binding molecules interact also with AGF receptors. In this review the authors summarize literature data and discuss the current knowledge about the extracellular molecules able to interact with AGFs, thus representing possible key regulators of the angiogenesis process and targets/templates for the development of novel antiangiogenic drugs. This work represents an attempt to highlight common theme in the AGF interactome that occurs at the extracellular level during neovascularization
Targeting fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis
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