ABSTRACT
BACKGROUND AND PURPOSE: Pathological angiogenesis is associated with various human diseases, such as cancer, autoimmune diseases and retinopathy. The angiopoietin (Ang)-Tie2 system plays critical roles in several steps of angiogenic remodelling. Here, we have investigated the anti-angiogenic effect of a novel angiopoietin-derived peptide. EXPERIMENTAL APPROACH: Using computational methods, we identified peptides from helical segments within angiopoietins, which were predicted to inhibit their activity. These peptides were tested using biochemical methods and models of angiogenesis. The peptide with best efficacy, A11, was selected for further characterization as an anti-angiogenic compound. KEY RESULTS: The potent anti-angiogenic activity of A11 was demonstrated in a multicellular assay of angiogenesis and in the chorioallantoic membrane model. A11 bound to angiopoietins and reduced the binding of Ang-2 to Tie2. A11 was also significantly reduced vascular density in a model of tumour-induced angiogenesis. Its ability to inhibit Ang-2 but not Ang-1-induced endothelial cell migration, and to down-regulate Tie2 levels in tumour microvessels, suggests that A11 targets the Ang-Tie2 pathway. In a rat model of oxygen-induced retinopathy, A11 strongly inhibited retinal angiogenesis. Moreover, combination of A11 with an anti-VEGF antibody showed a trend for further inhibition of angiogenesis, suggesting an additive effect. CONCLUSIONS AND IMPLICATIONS: Our results indicate that A11 is a potent anti-angiogenic compound, through modulation of the Ang-Tie2 system, underlining its potential as a therapeutic agent for the treatment of ocular and tumour neovascularization, as well as other pathological conditions that are dependent on angiogenesis.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Colorectal Neoplasms/drug therapy , Neovascularization, Pathologic/drug therapy , Peptides/therapeutic use , Retinal Neovascularization/drug therapy , Angiogenesis Inhibitors/pharmacology , Angiopoietins/metabolism , Animals , Cell Movement/drug effects , Chickens , Chorioallantoic Membrane/blood supply , Colorectal Neoplasms/pathology , Disease Models, Animal , Female , HCT116 Cells , Human Umbilical Vein Endothelial Cells/drug effects , Human Umbilical Vein Endothelial Cells/physiology , Humans , Mice , Mice, Nude , Neovascularization, Pathologic/pathology , Peptides/pharmacology , Rats , Rats, Sprague-Dawley , Retinal Neovascularization/pathology , Xenograft Model Antitumor AssaysABSTRACT
Following recent x-ray diffraction experiments by Wong, Li, and Safinya on biopolymer gels, we apply Onsager excluded volume theory to a nematic mixture of rigid rods and strong " pi/2" cross-linkers obtaining a long-ranged, highly anisotropic depletion attraction between the linkers. This attraction leads to breakdown of the percolation theory for this class of gels, to breakdown of Onsager's second-order virial method, and to formation of heterogeneities in the form of raftlike ribbons.
Subject(s)
Biopolymers/chemistry , Models, Chemical , Actin Cytoskeleton/chemistry , Actins/chemistry , Biophysical Phenomena , Biophysics , DNA/chemistry , Elasticity , Gels/chemistryABSTRACT
The behavior of mobile linkers connecting two semiflexible charged polymers, such as polyvalent counterions connecting DNA or F-actin chains, is studied theoretically. The chain bending rigidity induces an effective repulsion between linkers at large distances while the interchain electrostatic repulsion leads to an effective short-range interlinker attraction. We find a rounded phase transition from a dilute linker gas where the chains form large loops between linkers to a dense disordered linker fluid connecting parallel chains. The onset of chain pairing occurs within the rounded transition.
Subject(s)
Biopolymers/chemistry , Models, Chemical , Actins/chemistry , DNA/chemistry , Ions , Nucleic Acid Conformation , Protein Conformation , Static ElectricityABSTRACT
The interactions between spherical colloids covered with end-grafted polymers (brushes) immersed in a polymer melt are studied theoretically. We show that attractive enthalpic interactions between the two polymer species, characterized by a negative Flory parameter (chi<0), can stabilize the colloidal dispersion. The stabilizing mechanism is a result of a structural change from a dry brush, where the melt chains do not penetrate deeply into the brush, to a wet brush, where the free chains penetrate the brush and force the grafted chains to extend into the melt.
