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      Integrin-α9 is required for fibronectin matrix assembly during lymphatic valve morphogenesis

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          Dysfunction of lymphatic valves underlies human lymphedema, yet the process of valve morphogenesis is poorly understood. Here, we show that during embryogenesis lymphatic valve leaflet formation is initiated by upregulation of integrin-α9 expression and deposition of its ligand, fibronectin-EIIIA (FN-EIIIA), in the extracellular matrix. Endothelial cell specific deletion of Itga9 (encoding integrin-α9) in mouse embryos results in the development of rudimentary valve leaflets, characterized by disorganized FN matrix, short cusps and retrograde lymphatic flow. Similar morphological and functional defects are observed in mice lacking the EIIIA domain of FN. Mechanistically, we demonstrate that in primary human lymphatic endothelial cells the integrin-α9-EIIIA interaction directly regulates FN fibril assembly, which is essential for the formation of the extracellular matrix core of valve leaflets. Our findings reveal an important role for integrin-α9 signaling during lymphatic valve morphogenesis and implicate it as a candidate gene for primary lymphedema caused by valve defects.

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          Most cited references 40

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          Transmembrane crosstalk between the extracellular matrix--cytoskeleton crosstalk.

          Integrin-mediated cell adhesions provide dynamic, bidirectional links between the extracellular matrix and the cytoskeleton. Besides having central roles in cell migration and morphogenesis, focal adhesions and related structures convey information across the cell membrane, to regulate extracellular-matrix assembly, cell proliferation, differentiation, and death. This review describes integrin functions, mechanosensors, molecular switches and signal-transduction pathways activated and integrated by adhesion, with a unifying theme being the importance of local physical forces.
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            Integrins in angiogenesis and lymphangiogenesis.

            Blood vessels promote tumour growth, and both blood and lymphatic vessels facilitate tumour metastasis by serving as conduits for the transport of tumour cells to new sites. Angiogenesis and lymphangiogenesis are regulated by integrins, which are members of a family of cell surface receptors whose ligands are extracellular matrix proteins and immunoglobulin superfamily molecules. Select integrins promote endothelial cell migration and survival during angiogenesis and lymphangiogenesis, whereas other integrins promote pro-angiogenic macrophage trafficking to tumours. Several integrin-targeted therapeutic agents are currently in clinical trials for cancer therapy. Here, we review the evidence implicating integrins as a family of fundamental regulators of angiogenesis and lymphangiogenesis.
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              Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3.

              Vascular endothelial growth factor receptor-3 (VEGFR-3/Flt4) binds two known members of the VEGF ligand family, VEGF-C and VEGF-D, and has a critical function in the remodelling of the primary capillary vasculature of midgestation embryos. Later during development, VEGFR-3 regulates the growth and maintenance of the lymphatic vessels. In the present study, we have isolated and cultured stable lineages of blood vascular and lymphatic endothelial cells from human primary microvascular endothelium by using antibodies against the extracellular domain of VEGFR-3. We show that VEGFR-3 stimulation alone protects the lymphatic endothelial cells from serum deprivation-induced apoptosis and induces their growth and migration. At least some of these signals are transduced via a protein kinase C-dependent activation of the p42/p44 MAPK signalling cascade and via a wortmannin-sensitive induction of Akt phosphorylation. These results define the critical role of VEGF-C/VEGFR-3 signalling in the growth and survival of lymphatic endothelial cells. The culture of isolated lymphatic endothelial cells should now allow further studies of the molecular properties of these cells.

                Author and article information

                Dev Cell
                Dev. Cell
                Developmental cell
                10 September 2009
                August 2009
                01 August 2010
                : 17
                : 2
                : 175-186
                [1 ] Lymphatic Development Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom
                [2 ] Lung Biology Center, UCSF, San Francisco CA 94143-2922, USA
                [3 ] Electron Microscopy Unit, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom
                [4 ] Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan
                [5 ] Institute for Physiological Chemistry and Pathobiochemistry, Münster University, 48149 Münster, Germany
                [6 ] Vascular Development Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom
                [7 ] Max–Planck–Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, and University of Münster, Faculty of Medicine, 48149 Münster, Germany
                [8 ] International Centre for Genetic Engineering and Biotechnology, 34012 Trieste, Italy
                Author notes
                [* ] Corresponding author: taija.makinen@ , Phone: +44 207 269 3459, Fax: +44 207 269 3417

                Open Access under CC BY-NC-ND 3.0 license.


                Developmental biology


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