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      Fibrin and Collagen Differentially but Synergistically Regulate Sprout Angiogenesis of Human Dermal Microvascular Endothelial Cells in 3-Dimensional Matrix

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          Abstract

          Angiogenesis is a highly regulated event involving complex, dynamic interactions between microvascular endothelial cells and extracellular matrix (ECM) proteins. Alteration of ECM composition and architecture is a hallmark feature of wound clot and tumor stroma. We previously reported that during angiogenesis, endothelial cell responses to growth factors are modulated by the compositional and mechanical properties of a surrounding three-dimensional (3D) extracellular matrix (ECM) that is dominated by either cross-linked fibrin or type I collagen. However, the role of 3D ECM in the regulation of angiogenesis associated with wound healing and tumor growth is not well defined. This study investigates the correlation of sprout angiogenesis and ECM microenvironment using in vivo and in vitro 3D angiogenesis models. It demonstrates that fibrin and type I collagen 3D matrices differentially but synergistically regulate sprout angiogenesis. Thus blocking both integrin alpha v beta 3 and integrin alpha 2 beta 1 might be a novel strategy to synergistically block sprout angiogenesis in solid tumors.

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          Most cited references34

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          Angiogenesis in wound healing.

          During wound healing, angiogenic capillary sprouts invade the fibrin/fibronectin-rich wound clot and within a few days organize into a microvascular network throughout the granulation tissue. As collagen accumulates in the granulation tissue to produce scar, the density of blood vessels diminishes. A dynamic interaction occurs among endothelial cells, angiogenic cytokines, such as FGF, VEGF, TGF-beta, angiopoietin, and mast cell tryptase, and the extracellular matrix (ECM) environment. Specific endothelial cell ECM receptors are critical for these morphogenetic changes in blood vessels during wound repair. In particular, alpha(v)beta3, the integrin receptor for fibrin and fibronectin, appears to be required for wound angiogenesis: alpha(v)beta3 is expressed on the tips of angiogenic capillary sprouts invading the wound clot, and functional inhibitors of alpha(v)beta3 transiently inhibit granulation tissue formation. Recent investigations have shown that the wound ECM can regulate angiogenesis in part by modulating integrin receptor expression. mRNA levels of alpha(v)beta3 in human dermal microvascular endothelial cells either plated on fibronectin or overlaid by fibrin gel were higher than in cells plated on collagen or overlaid by collagen gel. Wound angiogenesis also appears to be regulated by endothelial cell interaction with the specific three-dimensional ECM environment in the wound space. In an in vitro model of human sprout angiogenesis, three-dimensional fibrin gel, simulating early wound clot, but not collagen gel, simulating late granulation tissue, supported capillary sprout formation. Understanding the molecular mechanisms that regulate wound angiogenesis, particularly how ECM modulates ECM receptor and angiogenic factor requirements, may provide new approaches for treating chronic wounds.
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            Endothelial extracellular matrix: biosynthesis, remodeling, and functions during vascular morphogenesis and neovessel stabilization.

            The extracellular matrix (ECM) is critical for all aspects of vascular biology. In concert with supporting cells, endothelial cells (ECs) assemble a laminin-rich basement membrane matrix that provides structural and organizational stability. During the onset of angiogenesis, this basement membrane matrix is degraded by proteinases, among which membrane-type matrix metalloproteinases (MT-MMPs) are particularly significant. As angiogenesis proceeds, ECM serves essential functions in supporting key signaling events involved in regulating EC migration, invasion, proliferation, and survival. Moreover, the provisional ECM serves as a pliable scaffold wherein mechanical guidance forces are established among distal ECs, thereby providing organizational cues in the absence of cell-cell contact. Finally, through specific integrin-dependent signal transduction pathways, ECM controls the EC cytoskeleton to orchestrate the complex process of vascular morphogenesis by which proliferating ECs organize into multicellular tubes with functional lumens. Thus, the composition of ECM and therefore the regulation of ECM degradation and remodeling serves pivotally in the control of lumen and tube formation and, finally, neovessel stability and maturation.
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              Requirement of vascular integrin alpha v beta 3 for angiogenesis.

              Angiogenesis depends on the adhesive interactions of vascular cells. The adhesion receptor integrin alpha v beta 3 was identified as a marker of angiogenic vascular tissue. Integrin alpha v beta 3 was expressed on blood vessels in human wound granulation tissue but not in normal skin, and it showed a fourfold increase in expression during angiogenesis on the chick chorioallantoic membrane. In the latter assay, a monoclonal antibody to alpha v beta 3 blocked angiogenesis induced by basic fibroblast growth factor, tumor necrosis factor-alpha, and human melanoma fragments but had no effect on preexisting vessels. These findings suggest that alpha v beta 3 may be a useful therapeutic target for diseases characterized by neovascularization.
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                Author and article information

                Journal
                Int J Cell Biol
                Int J Cell Biol
                IJCB
                International Journal of Cell Biology
                Hindawi Publishing Corporation
                1687-8876
                1687-8884
                2013
                30 April 2013
                : 2013
                : 231279
                Affiliations
                1Department of Clinical and Administrative Sciences, California Northstate University College of Pharmacy, Rancho Cordova, CA 95670, USA
                2Department of Dermatology, School of Medicine, State University of New York at Stony Brook, Stony Brook, NY 11794, USA
                3Dermatology Section, Veterans Affairs Medical Center, Northport, NY 11768, USA
                4Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY 12208, USA
                5Center for Tissue Engineering, State University of New York at Stony Brook, Stony Brook, NY 11794, USA
                Author notes
                *Xiaodong Feng: xfeng@ 123456cnsu.edu

                Academic Editor: Michael Peter Sarras

                Author information
                https://orcid.org/0000-0002-4495-117X
                Article
                10.1155/2013/231279
                3657431
                23737792
                d43a4385-e309-4e39-99ca-65f281467628
                Copyright © 2013 Xiaodong Feng et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 29 January 2013
                : 27 March 2013
                : 10 April 2013
                Categories
                Research Article

                Cell biology
                Cell biology

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