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J. Biol. Chem., Vol. 279, Issue 51, 52904-52913, December 17, 2004

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Matrix GLA Protein Stimulates VEGF Expression through Increased Transforming Growth Factor-1 Activity in Endothelial Cells^*

Kristina Boström¶, Amina F. Zebboudj, Yucheng Yao, Than S. Lin, and Alejandra Torres

From the Division of Cardiology, David Geffen School of Medicine, and the Molecular Biology Institute, University of California, Los Angeles, California 90095-1679

Matrix GLA protein (MGP) is expressed in endothelial cells (EC), and MGP deficiency results in developmental defects suggesting involvement in EC function. To determine the role of MGP in EC, we cultured bovine aortic EC with increasing concentrations of human MGP (hMGP) for 24 h. The results showed increased proliferation, migration, tube formation, and increased release of vascular endothelial growth factor-A (VEGF-A) and basic fibroblast growth factor (bFGF). HMGP, added endogenously or transiently expressed, increased VEGF gene expression dose-dependently as determined by real-time PCR. To determine the mechanism by which hMGP increased VEGF expression, we studied the effect of MGP on the activity of transforming growth factor (TGF)-1 compared with that of bone morphogenetic protein (BMP)-2 using transfection assays with TGF-- and BMP-response element reporter genes. Our results showed a strong enhancement of TGF-1 activity by hMGP, which was paralleled by increased VEGF expression. BMP-2 activity, on the other hand, was inhibited by hMGP. Neutralizing antibodies to TGF- blocked the effect of MGP on VEGF expression. The enhanced TGF-1 activity specifically activated the Smad1/5 pathway indicating that the TGF- receptor activin-like kinase 1 (ALK1) had been stimulated. It occurred without changes in expression of TGF-1 or ALK1 and was mimicked by transfection of constitutively active ALK1, which increased VEGF expression. Expression of VEGF and MGP was induced by TGF-1, but the induction of MGP preceded that of VEGF, consistent with a promoting effect on VEGF expression. Together, the results suggest that MGP plays a role in EC function, altering the response to TGF- superfamily growth factors.

Received for publication, June 21, 2004 , and in revised form, September 7, 2004.

^* This work was funded in part by National Institutes of Health Grants HL04270 and HL030568, by the American Heart Association (National), and by the Laubisch Fund. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Division of Cardiology, David Geffen School of Medicine at UCLA, Box 951679, Rm. 47-123 CHS, Los Angeles, CA 90095-1679. Tel.: 310-794-4417; Fax: 310-206-9133; E-mail: kbostrom{at}mednet.ucla.edu.

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