The chemokine receptor CXCR7 functions to regulate cardiac valve remodeling

Authors

  • Sangho Yu,

    1. Gladstone Institute of Cardiovascular Disease, San Francisco, California
    2. Department of Biochemistry & Biophysics, University of California, San Francisco, California
    3. Department of Pediatrics, University of California, San Francisco, California
    Current affiliation:
    1. Sangho Yu and Dianna Crawford contributed equally to this work.
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  • Dianna Crawford,

    1. Center for Immunology, Department of Medicine, University of Minnesota Medical School, University of Minnesota, Minneapolis, Minnesota
    Current affiliation:
    1. Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320.
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  • Takatoshi Tsuchihashi,

    1. Gladstone Institute of Cardiovascular Disease, San Francisco, California
    2. Department of Biochemistry & Biophysics, University of California, San Francisco, California
    3. Department of Pediatrics, University of California, San Francisco, California
    Current affiliation:
    1. Division of Cardiology, Department of Pediatrics, School of Medicine, Keio University, 35 Shinanomachi Shinjuku-ku, Tokyo, Japan 160-8582.
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  • Timothy W. Behrens,

    1. Center for Immunology, Department of Medicine, University of Minnesota Medical School, University of Minnesota, Minneapolis, Minnesota
    Current affiliation:
    1. Genentech Inc., 1 DNA Way, South San Francisco, CA 94080.
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  • Deepak Srivastava

    Corresponding author
    1. Gladstone Institute of Cardiovascular Disease, San Francisco, California
    2. Department of Biochemistry & Biophysics, University of California, San Francisco, California
    3. Department of Pediatrics, University of California, San Francisco, California
    • Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, CA 94158
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Abstract

CXCR7 (RDC1), a G-protein-coupled receptor with conserved motifs characteristic of chemokine receptors, is enriched in endocardial and cushion mesenchymal cells in developing hearts, but its function is unclear. Cxcr7 germline deletion resulted in perinatal lethality with complete penetrance. Mutant embryos exhibited aortic and pulmonary valve stenosis due to semilunar valve thickening, with occasional ventricular septal defects. Semilunar valve mesenchymal cell proliferation increased in mutants from embryonic day 14 onward, but the cell death rate remained unchanged. Cxcr7 mutant valves had increased levels of phosphorylated Smad1/5/8, indicating increased BMP signaling, which may partly explain the thickened valve leaflets. The hyperproliferative phenotype appeared to involve Cxcr7 function in endocardial cells and their mesenchymal derivatives, as Tie2-Cre Cxcr7flox/− mice had semilunar valve stenosis. Thus, CXCR7 is involved in semilunar valve development, possibly by regulating BMP signaling, and may contribute to aortic and pulmonary valve stenosis. Developmental Dynamics 240:384–393, 2011. © 2011 Wiley-Liss, Inc.

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