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      Saxatilin, a Snake Venom Disintegrin, Regulates Platelet Activation Associated with Human Vascular Endothelial Cell Migration and Invasion

      , ,

      Journal of Vascular Research

      S. Karger AG

      Angiogenesis, Platelet, Saxatilin, Endothelial cell, Chemotaxis

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          Background: Platelet activation results in platelet aggregation and the secretion of granules, which contain a variety of constituents including nonprotein molecules, adhesive proteins and hydrolases. The platelet-derived supernatant (PDS), which contains these granules, is known to trigger the activation of endothelium and chemotaxis of monocytes. Methods and Results: PDS derived from collagen-activated platelets stimulated human umbilical vein endothelial cell (HUVEC) migration and invasion, as measured through the use of a Boyden chamber. This collagen-induced PDS also triggered integrin α<sub>v</sub>β<sub>3</sub> upregulation in HUVECs. The inclusion of a neutralizing antibody to platelet-derived growth factor (PDGF)-B abolished HUVEC migration/invasion and integrin α<sub>v</sub>β<sub>3</sub> upregulation, showing that PDGF-AB mediates the proangiogenic effects of collagen-activated PDS. Saxatilin, a snake venom disintegrin known to interrupt platelet aggregation by antagonizing integrin α<sub>IIb</sub>β<sub>3</sub>, inhibited the collagen-induced platelet activation and abolished the angiogenic properties of PDS. Saxatilin also inhibited the collagen-induced phosphorylation of Syk, a key mediator of inside-out signaling in platelet activation. Conclusion: Saxatilin inhibits platelet activation, platelet PDGF-AB release as well as subsequent endothelial cell migration and invasion.

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          Most cited references 30

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          Vascular-specific growth factors and blood vessel formation.

          A recent explosion in newly discovered vascular growth factors has coincided with exploitation of powerful new genetic approaches for studying vascular development. An emerging rule is that all of these factors must be used in perfect harmony to form functional vessels. These new findings also demand re-evaluation of therapeutic efforts aimed at regulating blood vessel growth in ischaemia, cancer and other pathological settings.
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            PDGF, TGF-β, and Heterotypic Cell–Cell Interactions Mediate Endothelial Cell–induced Recruitment of 10T1/2 Cells and Their Differentiation to a Smooth Muscle Fate

            We aimed to determine if and how endothelial cells (EC) recruit precursors of smooth muscle cells and pericytes and induce their differentiation during vessel formation. Multipotent embryonic 10T1/2 cells were used as presumptive mural cell precursors. In an under-agarose coculture, EC induced migration of 10T1/2 cells via platelet-derived growth factor BB. 10T1/2 cells in coculture with EC changed from polygonal to spindle-shaped, reminiscent of smooth muscle cells in culture. Immunohistochemical and Western blot analyses were used to examine the expression of smooth muscle (SM)-specific markers in 10T1/2 cells cultured in the absence and presence of EC. SM-myosin, SM22α, and calponin proteins were undetectable in 10T1/2 cells cultured alone; however, expression of all three SM-specific proteins was significantly induced in 10T1/2 cells cocultured with EC. Treatment of 10T1/2 cells with TGF-β induced phenotypic changes and changes in SM markers similar to those seen in the cocultures. Neutralization of TGF-β in the cocultures blocked expression of the SM markers and the shape change. To assess the ability of 10T1/2 cells to contribute to the developing vessel wall in vivo, prelabeled 10T1/2 cells were grown in a collagen matrix and implanted subcutaneously into mice. The fluorescently marked cells became incorporated into the medial layer of developing vessels where they expressed SM markers. These in vitro and in vivo observations shed light on the cell–cell interactions that occur during vessel development, as well as in pathologies in which developmental processes are recapitulated.
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              Platelets in inflammation and thrombosis.

              For many years it has been known that platelets play an important role in thrombosis and hemostasis. In recent times, however, it has become evident that platelets also have relevant functions in inflammation. It was shown that thrombosis and inflammation share several key molecular mechanisms and in fact are 2 intrinsically linked processes. In this review, we intend to give a short overview with emphasis on work stemming from our laboratory.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                February 2007
                11 January 2007
                : 44
                : 2
                : 129-137
                Department of Biochemistry, College of Science, Yonsei University, Seoul, Republic of Korea
                98519 J Vasc Res 2007;44:129–137
                © 2007 S. Karger AG, Basel

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                Page count
                Figures: 5, References: 50, Pages: 9
                Research Paper


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