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      Adhesion of Endothelial Cells to NOV Is Mediated by the Integrins αvβ3 and α5β1

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          NOV is a member of the CCN family of matricellular proteins. We have shown previously that Nov is strongly expressed by vascular smooth muscle cells (VSMCs) of the rat carotid artery. However, 7 days after injury, Nov expression is down-regulated, except near the luminal surface of the developing intima, where it is strongly expressed. These data suggested that NOV might be involved in the regulation of endothelial cell adhesion. NOV promoted the adhesion of human umbilical vein endothelial cells (HUVECs), which was abolished by anti-NOV antibody. HUVEC adhesion to NOV required divalent cations and was inhibited by GRGDS peptide, implicating integrins in the adhesion mechanism. Monoclonal antibodies (mAbs) against αvβ3 inhibited adhesion of HUVECs to NOV, and NOV was shown to bind to αvβ3. Anti-α5β1 mAbs also inhibited HUVEC adhesion to NOV, but adhesion via α5β1 was mediated by fibronectin. HUVEC adhesion to NOV caused intracellular signalling, as evidenced by increased phosphotyrosine content of focal adhesion kinase. Together with evidence that Nov expression in a variety of tissues is restricted to blood vessels containing VSMCs, these data are consistent with a role for NOV in endothelial cell adhesion in vascular homeostasis and in the response to injury.

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          Most cited references 12

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          RGD and other recognition sequences for integrins.

           E Ruoslahti (1995)
          Proteins that contain the Arg-Gly-Asp (RGD) attachment site, together with the integrins that serve as receptors for them, constitute a major recognition system for cell adhesion. The RGD sequence is the cell attachment site of a large number of adhesive extracellular matrix, blood, and cell surface proteins, and nearly half of the over 20 known integrins recognize this sequence in their adhesion protein ligands. Some other integrins bind to related sequences in their ligands. The integrin-binding activity of adhesion proteins can be reproduced by short synthetic peptides containing the RGD sequence. Such peptides promote cell adhesion when insolubilized onto a surface, and inhibit it when presented to cells in solution. Reagents that bind selectively to only one or a few of the RGD-directed integrins can be designed by cyclizing peptides with selected sequences around the RGD and by synthesizing RGD mimics. As the integrin-mediated cell attachment influences and regulates cell migration, growth, differentiation, and apoptosis, the RGD peptides and mimics can be used to probe integrin functions in various biological systems. Drug design based on the RGD structure may provide new treatments for diseases such as thrombosis, osteoporosis, and cancer.
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            The modular architecture of a new family of growth regulators related to connective tissue growth factor.

             P. Bork (1993)
            Recently, several groups have characterized and sequenced members of a new family of growth regulators (originally called cef10, connective tissue growth factor, fisp-12, cyr61, or, alternatively, beta IG-M1 and beta IG-M2), all of which belong to immediate-early genes expressed after induction by growth factors or certain oncogenes. Sequence analysis of this family revealed the presence of four distinct modules. Each module has homologues in other extracellular mosaic proteins such as Von Willebrand factor, slit, thrombospondins, fibrillar collagens, IGF-binding proteins and mucins. Classification and analysis of these modules suggests the location of binding regions and, by analogy to better characterized modules in other proteins, sheds some light onto the structure of this new family.
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              CYR61 (CCN1) is essential for placental development and vascular integrity.

              CYR61 (CCN1) is a member of the CCN family of secreted matricellular proteins that includes connective tissue growth factor (CCN2), NOV (CCN3), WISP-1 (CCN4), WISP-2 (CCN5), and WISP-3 (CCN6). First identified as the product of a growth factor-inducible immediate-early gene, CYR61 is an extracellular matrix-associated angiogenic inducer that functions as a ligand of integrin receptors to promote cell adhesion, migration, and proliferation. Aberrant expression of Cyr61 is associated with breast cancer, wound healing, and vascular diseases such as atherosclerosis and restenosis. To understand the functions of CYR61 during development, we have disrupted the Cyr61 gene in mice. We show here that Cyr61-null mice suffer embryonic death: approximately 30% succumbed to a failure in chorioallantoic fusion, and the reminder perished due to placental vascular insufficiency and compromised vessel integrity. These findings establish CYR61 as a novel and essential regulator of vascular development. CYR61 deficiency results in a specific defect in vessel bifurcation (nonsprouting angiogenesis) at the chorioallantoic junction, leading to an undervascularization of the placenta without affecting differentiation of the labyrinthine syncytiotrophoblasts. This unique phenotype is correlated with impaired Vegf-C expression in the allantoic mesoderm, suggesting that CYR61-regulated expression of Vegf-C plays a role in vessel bifurcation. The genetic and molecular basis of vessel bifurcation is presently unknown, and these findings provide new insight into this aspect of angiogenesis.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                June 2003
                08 August 2003
                : 40
                : 3
                : 234-243
                aSection of Cardiovascular Biology, bDepartment of Biochemistry, University of Cambridge, Cambridge, UK
                71887 J Vasc Res 2003;40:234–243
                © 2003 S. Karger AG, Basel

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                Page count
                Figures: 5, References: 29, Pages: 10
                Research Paper


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