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J. Biol. Chem., Vol. 282, Issue 41, 30131-30142, October 12, 2007

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Matrix GLA Protein, an Inhibitory Morphogen in Pulmonary Vascular Development^*

Yucheng Yao, Sarah Nowak, Arik Yochelis, Alan Garfinkel, and Kristina I. Boström^¶1

From the Division of Cardiology, David Geffen School of Medicine, UCLA, Los Angeles, California 90095-1679, the Department of Biomathematics, David Geffen School of Medicine, UCLA, Los Angeles, California 90095-1766, and the ^¶Molecular Biology Institute, UCLA, Los Angeles, California 90095-1570

Deficiency of matrix GLA protein (MGP), an inhibitor of bone morphogenetic protein (BMP)-2/4, is known to cause arterial calcification and peripheral pulmonary artery stenosis. Yet the vascular role of MGP remains poorly understood. To further investigate MGP, we created a new MGP transgenic mouse model with high expression of the transgene in the lungs. The excess MGP led to a disruption of the pulmonary pattern of BMP-4, and resulted in significant morphological defects in the pulmonary artery tree. Specifically, the vascular branching pattern lacked characteristic side branching, whereas control lungs had extensive side branching accounting for as much as 40% of the vascular endothelium. The vascular changes could be explained by a dramatic reduction of phosphorylated SMAD1/5/8 in the alveolar epithelium, and in epithelial expression of the activin-like kinase receptor 1 and vascular endothelial growth factor, both critical in vascular formation. Abnormalities were also found in the terminal airways and in lung cell differentiation; high levels of surfactant protein-B were distributed in an abnormal pattern suggesting lost coordination between vasculature and airways. Ex vivo, lung cells from MGP transgenic mice showed higher proliferation, in particular surfactant protein B-expressing cells, and conditioned medium from these cells poorly supported in vitro angiogenesis compared with normal lung cells. The vascular branching defect can be mechanistically explained by a computational model based on activator/inhibitor reaction-diffusion dynamics, where BMP-4 and MGP are considered as an activating and inhibitory morphogen, respectively, suggesting that morphogen interactions are important for vascular branching.

Received for publication, May 24, 2007 , and in revised form, August 1, 2007.

^* This work was supported in part by National Institutes of Health Grants HL30568, HL81397, and HL78931 and the American Heart Association (Western Affiliate). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental movie 1.

¹ To whom correspondence should be addressed: Box 951679, Los Angeles, CA 90095-1679. Tel.: 310-794-4417; Fax: 310-206-9133; E-mail: kbostrom{at}mednet.ucla.edu.

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