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Syndecan-1 regulates _vβ₃ and _vβ₅ integrin activation during angiogenesis and is blocked by synstatin, a novel peptide inhibitor

Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI 53706

CORRESPONDENCE Alan C. Rapraeger: acraprae{at}wisc.edu

Syndecan-1 (Sdc1) is a matrix receptor shown to associate via its extracellular domain with the _vβ₃ and _vβ₅ integrins, potentially regulating cell adhesion, spreading, and invasion of cells expressing these integrins. Using Sdc1 deletion mutants expressed in human mammary carcinoma cells, we identified the active site within the Sdc1 core protein and derived a peptide inhibitor called synstatin (SSTN) that disrupts Sdc1's interaction with these integrins. Because the _vβ₃ and _vβ₅ integrins are critical in angiogenesis, a process in which a role for Sdc1 has been uncertain, we used human vascular endothelial cells in vitro to show that the Sdc1 regulatory mechanism is also required for integrin activation on these cells. We found Sdc1 expressed in the vascular endothelium during microvessel outgrowth from aortic explants in vitro and in mouse mammary tumors in vivo. Moreover, we show that SSTN blocks angiogenesis in vitro or when delivered systemically in a mouse model of angiogenesis in vivo, and impairs mammary tumor growth in an orthotopic mouse tumor model. Thus, Sdc1 is a critical regulator of these two important integrins during angiogenesis and tumorigenesis, and is inhibited by the novel SSTN peptide.

Abbreviations used: FGF, fibroblast growth factor; FN, fibronectin; GST, glutathione S-transferase; HAEC, human aortic endothelial cell; HMEC-1, human dermal microvascular endothelial cell; HS, heparan sulfate; hSdc1, human Sdc1; HUVEC, human umbilical vein endothelial cell; MAEC, mouse aortic endothelial cell; mSdc1, mouse Sdc1; OCT, optimum cutting temperature; PECAM-1, platelet–endothelial cell adhesion molecule–1; Poly-HEMA, poly(2-hydroxyethyl methacrylate); siRNA, small interfering RNA; Sdc1, syndecan-1; S1ED, Sdc1 extracellular domain; SSTN, synstatin; VEGF, vascular endothelial growth factor; VN, vitronectin.

© 2009 Beauvais et al.
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This article has been cited by other articles:

• Beauvais, D. M., Ell, B. J., McWhorter, A. R., Rapraeger, A. C. (2009). Syndecan-1 regulates {alpha}v{beta}3 and {alpha}v{beta}5 integrin activation during angiogenesis and is blocked by synstatin, a novel peptide inhibitor. JCB 184: i12-i12 [Full Text]  

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