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J. Biol. Chem., Vol. 281, Issue 45, 33921-33930, November 10, 2006

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Regulation of Bone Morphogenetic Protein-4 by Matrix GLA Protein in Vascular Endothelial Cells Involves Activin-like Kinase Receptor 1^*

Yucheng Yao, Amina F. Zebboudj, Esther Shao, Martin Perez, and Kristina Boström¹

From the Division of Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095-1679 and the Molecular Biology Institute, UCLA, Los Angeles, California 90095-1570

Matrix GLA protein (MGP) has previously been shown to enhance expression of vascular endothelial growth factor (VEGF) through the activin-like kinase receptor 1 (ALK1) in bovine aortic endothelial cells. MGP has also been identified as an inhibitor of bone morphogenetic protein-2 (BMP-2). This study showed that the effect of MGP on ALK1 signaling and VEGF expression in bovine aortic endothelial cells was dose-dependent, that a progressive increase of MGP levels ceased to be stimulatory and instead turned inhibitory. We identified a new regulatory pathway involving BMP that may explain this response. BMP-2 and BMP-4 induced expression of ALK1 in a dose-dependent fashion as determined by real-time PCR and immunoblotting. Activation of ALK1 signaling induced expression of MGP in addition to that of VEGF, allowing for negative feedback regulation of BMP by MGP. MGP inhibited BMP-4 activity similarly to that of BMP-2 and interacted with BMP-4 on a protein level as determined by co-immunoprecipitation. The dose-dependent effect on ALK1 expression and the stimulation of MGP and VEGF expression were dependent on signaling by transforming growth factor- (TGF-) and ALK1. Inhibition of TGF- by neutralizing antibodies abolished the inhibitory effect of high BMP-4 levels on ALK1 expression and the induction of MGP and VEGF. Depletion of ALK1 by small interfering RNA abolished the induction of MGP and VEGF. MGP promoter activity was also stimulated by BMP-4 in a TGF--dependent fashion. The results suggest that the effects of BMP on endothelial cells occur in part through induction of ALK1, an effect that may be limited by ALK1-induced MGP.

Received for publication, May 3, 2006 , and in revised form, July 20, 2006.

^* This work was funded in by National Institutes of Health Grant HL04270, National Institutes of Health Grant HL30568, and National Institutes of Health Grant HL81397 and by grants from the American Heart Association (National and Western) and 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.

¹ To whom correspondence should be addressed: David Geffen School of Medicine at UCLA, Div. of Cardiology, Box 951679, Los Angeles, CA 90095-1679. Tel.: 310-794-4417; Fax: 310-206-8553; E-mail: kbostrom{at}mednet.ucla.edu.

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