{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T22:08:40Z","timestamp":1793398120975,"version":"4.5.0"},"reference-count":17,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2011,8,19]]},"abstract":"<jats:sec>\n                    <jats:title>\n                      <jats:underline>Rationale:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>Collagen- and calcium-binding EGF domains 1 (CCBE1) has been associated with Hennekam syndrome, in which patients have lymphedema, lymphangiectasias, and other cardiovascular anomalies. Insight into the molecular role of CCBE1 is completely lacking, and mouse models for the disease do not exist.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Objective:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>CCBE1 deficient mice were generated to understand the function of CCBE1 in cardiovascular development, and CCBE1 recombinant protein was used in both in vivo and in vitro settings to gain insight into the molecular function of CCBE1.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Methods and Results:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>\n                      Phenotypic analysis of murine\n                      <jats:italic>Ccbe1<\/jats:italic>\n                      mutant embryos showed a complete lack of definitive lymphatic structures, even though Prox1\n                      <jats:sup>+<\/jats:sup>\n                      lymphatic endothelial cells get specified within the cardinal vein. Mutant mice die prenatally. Proximity ligation assays indicate that vascular endothelial growth factor receptor 3 activation appears unaltered in mutants. Human CCBE1 protein binds to components of the extracellular matrix in vitro, and CCBE1 protein strongly enhances vascular endothelial growth factor-C\u2013mediated lymphangiogenesis in a corneal micropocket assay.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Conclusions:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>\n                      Our data identify CCBE1 as a factor critically required for budding and migration of Prox-1\n                      <jats:sup>+<\/jats:sup>\n                      lymphatic endothelial cells from the cardinal vein. CCBE1 probably exerts these effects through binding to components of the extracellular matrix. CCBE1 has little lymphangiogenic effect on its own but dramatically enhances the lymphangiogenic effect of vascular endothelial growth factor-C in vivo. Thus, our data suggest CCBE1 to be essential but not sufficient for lymphangiogenesis.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.111.250738","type":"journal-article","created":{"date-parts":[[2011,7,21]],"date-time":"2011-07-21T23:11:40Z","timestamp":1311289900000},"page":"486-491","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":195,"title":["CCBE1 Is Essential for Mammalian Lymphatic Vascular Development and Enhances the Lymphangiogenic Effect of Vascular Endothelial Growth Factor-C In Vivo"],"prefix":"10.1161","volume":"109","author":[{"given":"Frank L.","family":"Bos","sequence":"first","affiliation":[{"name":"From the Hubrecht Institute-KNAW and UMC Utrecht, Utrecht, The Netherlands (F.L.B., J.P.-M., T.K., A.v.I., J.K., J.H.v.E., S.S.-M.); EMC, Rotterdam, The Netherlands (F.L.B., H.J.D.); the Molecular Biology Department, Genentech Inc, South San Francisco, CA (M.C., J.K.); the Institute of Metabolic Physiology, Heinrich Heine Universit\u00e4t D\u00fcsseldorf, D\u00fcsseldorf, Germany (L.P.-P., E.L.); the Protein Chemistry Department, Genentech Inc, South San Francisco, CA (R.T., J.A.E.); and EZO Department, University..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maresa","family":"Caunt","sequence":"additional","affiliation":[{"name":"From the Hubrecht Institute-KNAW and UMC Utrecht, Utrecht, The Netherlands (F.L.B., J.P.-M., T.K., A.v.I., J.K., J.H.v.E., S.S.-M.); EMC, Rotterdam, The Netherlands (F.L.B., H.J.D.); the Molecular Biology Department, Genentech Inc, South San Francisco, CA (M.C., J.K.); the Institute of Metabolic Physiology, Heinrich Heine Universit\u00e4t D\u00fcsseldorf, D\u00fcsseldorf, Germany (L.P.-P., E.L.); the Protein Chemistry Department, Genentech Inc, South San Francisco, CA (R.T., J.A.E.); and EZO Department, University..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josi","family":"Peterson-Maduro","sequence":"additional","affiliation":[{"name":"From the Hubrecht Institute-KNAW and UMC Utrecht, Utrecht, The Netherlands (F.L.B., J.P.-M., T.K., A.v.I., J.K., J.H.v.E., S.S.-M.); EMC, Rotterdam, The Netherlands (F.L.B., H.J.D.); the Molecular Biology Department, Genentech Inc, South San Francisco, CA (M.C., J.K.); the Institute of Metabolic Physiology, Heinrich Heine Universit\u00e4t D\u00fcsseldorf, D\u00fcsseldorf, Germany (L.P.-P., E.L.); the Protein Chemistry Department, Genentech Inc, South San Francisco, CA (R.T., J.A.E.); and EZO Department, University..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lara","family":"Planas-Paz","sequence":"additional","affiliation":[{"name":"From the Hubrecht Institute-KNAW and UMC Utrecht, Utrecht, The Netherlands (F.L.B., J.P.-M., T.K., A.v.I., J.K., J.H.v.E., S.S.-M.); EMC, Rotterdam, The Netherlands (F.L.B., H.J.D.); the Molecular Biology Department, Genentech Inc, South San Francisco, CA (M.C., J.K.); the Institute of Metabolic Physiology, Heinrich Heine Universit\u00e4t D\u00fcsseldorf, D\u00fcsseldorf, Germany (L.P.-P., E.L.); the Protein Chemistry Department, Genentech Inc, South San Francisco, CA (R.T., J.A.E.); and EZO Department, University..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joe","family":"Kowalski","sequence":"additional","affiliation":[{"name":"From the Hubrecht Institute-KNAW and UMC Utrecht, Utrecht, The Netherlands (F.L.B., J.P.-M., T.K., A.v.I., J.K., J.H.v.E., S.S.-M.); EMC, Rotterdam, The Netherlands (F.L.B., H.J.D.); the Molecular Biology Department, Genentech Inc, South San Francisco, CA (M.C., J.K.); the Institute of Metabolic Physiology, Heinrich Heine Universit\u00e4t D\u00fcsseldorf, D\u00fcsseldorf, Germany (L.P.-P., E.L.); the Protein Chemistry Department, Genentech Inc, South San Francisco, CA (R.T., J.A.E.); and EZO Department, University..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terhi","family":"Karpanen","sequence":"additional","affiliation":[{"name":"From the Hubrecht Institute-KNAW and UMC Utrecht, Utrecht, The Netherlands (F.L.B., J.P.-M., T.K., A.v.I., J.K., J.H.v.E., S.S.-M.); EMC, Rotterdam, The Netherlands (F.L.B., H.J.D.); the Molecular Biology Department, Genentech Inc, South San Francisco, CA (M.C., J.K.); the Institute of Metabolic Physiology, Heinrich Heine Universit\u00e4t D\u00fcsseldorf, D\u00fcsseldorf, Germany (L.P.-P., E.L.); the Protein Chemistry Department, Genentech Inc, South San Francisco, CA (R.T., J.A.E.); and EZO Department, University..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"van Impel","sequence":"additional","affiliation":[{"name":"From the Hubrecht Institute-KNAW and UMC Utrecht, Utrecht, The Netherlands (F.L.B., J.P.-M., T.K., A.v.I., J.K., J.H.v.E., S.S.-M.); EMC, Rotterdam, The Netherlands (F.L.B., H.J.D.); the Molecular Biology Department, Genentech Inc, South San Francisco, CA (M.C., J.K.); the Institute of Metabolic Physiology, Heinrich Heine Universit\u00e4t D\u00fcsseldorf, D\u00fcsseldorf, Germany (L.P.-P., E.L.); the Protein Chemistry Department, Genentech Inc, South San Francisco, CA (R.T., J.A.E.); and EZO Department, University..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond","family":"Tong","sequence":"additional","affiliation":[{"name":"From the Hubrecht Institute-KNAW and UMC Utrecht, Utrecht, The Netherlands (F.L.B., J.P.-M., T.K., A.v.I., J.K., J.H.v.E., S.S.-M.); EMC, Rotterdam, The Netherlands (F.L.B., H.J.D.); the Molecular Biology Department, Genentech Inc, South San Francisco, CA (M.C., J.K.); the Institute of Metabolic Physiology, Heinrich Heine Universit\u00e4t D\u00fcsseldorf, D\u00fcsseldorf, Germany (L.P.-P., E.L.); the Protein Chemistry Department, Genentech Inc, South San Francisco, CA (R.T., J.A.E.); and EZO Department, University..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James A.","family":"Ernst","sequence":"additional","affiliation":[{"name":"From the Hubrecht Institute-KNAW and UMC Utrecht, Utrecht, The Netherlands (F.L.B., J.P.-M., T.K., A.v.I., J.K., J.H.v.E., S.S.-M.); EMC, Rotterdam, The Netherlands (F.L.B., H.J.D.); the Molecular Biology Department, Genentech Inc, South San Francisco, CA (M.C., J.K.); the Institute of Metabolic Physiology, Heinrich Heine Universit\u00e4t D\u00fcsseldorf, D\u00fcsseldorf, Germany (L.P.-P., E.L.); the Protein Chemistry Department, Genentech Inc, South San Francisco, CA (R.T., J.A.E.); and EZO Department, University..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeroen","family":"Korving","sequence":"additional","affiliation":[{"name":"From the Hubrecht Institute-KNAW and UMC Utrecht, Utrecht, The Netherlands (F.L.B., J.P.-M., T.K., A.v.I., J.K., J.H.v.E., S.S.-M.); EMC, Rotterdam, The Netherlands (F.L.B., H.J.D.); the Molecular Biology Department, Genentech Inc, South San Francisco, CA (M.C., J.K.); the Institute of Metabolic Physiology, Heinrich Heine Universit\u00e4t D\u00fcsseldorf, D\u00fcsseldorf, Germany (L.P.-P., E.L.); the Protein Chemistry Department, Genentech Inc, South San Francisco, CA (R.T., J.A.E.); and EZO Department, University..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan H.","family":"van Es","sequence":"additional","affiliation":[{"name":"From the Hubrecht Institute-KNAW and UMC Utrecht, Utrecht, The Netherlands (F.L.B., J.P.-M., T.K., A.v.I., J.K., J.H.v.E., S.S.-M.); EMC, Rotterdam, The Netherlands (F.L.B., H.J.D.); the Molecular Biology Department, Genentech Inc, South San Francisco, CA (M.C., J.K.); the Institute of Metabolic Physiology, Heinrich Heine Universit\u00e4t D\u00fcsseldorf, D\u00fcsseldorf, Germany (L.P.-P., E.L.); the Protein Chemistry Department, Genentech Inc, South San Francisco, CA (R.T., J.A.E.); and EZO Department, University..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eckhard","family":"Lammert","sequence":"additional","affiliation":[{"name":"From the Hubrecht Institute-KNAW and UMC Utrecht, Utrecht, The Netherlands (F.L.B., J.P.-M., T.K., A.v.I., J.K., J.H.v.E., S.S.-M.); EMC, Rotterdam, The Netherlands (F.L.B., H.J.D.); the Molecular Biology Department, Genentech Inc, South San Francisco, CA (M.C., J.K.); the Institute of Metabolic Physiology, Heinrich Heine Universit\u00e4t D\u00fcsseldorf, D\u00fcsseldorf, Germany (L.P.-P., E.L.); the Protein Chemistry Department, Genentech Inc, South San Francisco, CA (R.T., J.A.E.); and EZO Department, University..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henricus J.","family":"Duckers","sequence":"additional","affiliation":[{"name":"From the Hubrecht Institute-KNAW and UMC Utrecht, Utrecht, The Netherlands (F.L.B., J.P.-M., T.K., A.v.I., J.K., J.H.v.E., S.S.-M.); EMC, Rotterdam, The Netherlands (F.L.B., H.J.D.); the Molecular Biology Department, Genentech Inc, South San Francisco, CA (M.C., J.K.); the Institute of Metabolic Physiology, Heinrich Heine Universit\u00e4t D\u00fcsseldorf, D\u00fcsseldorf, Germany (L.P.-P., E.L.); the Protein Chemistry Department, Genentech Inc, South San Francisco, CA (R.T., J.A.E.); and EZO Department, University..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Schulte-Merker","sequence":"additional","affiliation":[{"name":"From the Hubrecht Institute-KNAW and UMC Utrecht, Utrecht, The Netherlands (F.L.B., J.P.-M., T.K., A.v.I., J.K., J.H.v.E., S.S.-M.); EMC, Rotterdam, The Netherlands (F.L.B., H.J.D.); the Molecular Biology Department, Genentech Inc, South San Francisco, CA (M.C., J.K.); the Institute of Metabolic Physiology, Heinrich Heine Universit\u00e4t D\u00fcsseldorf, D\u00fcsseldorf, Germany (L.P.-P., E.L.); the Protein Chemistry Department, Genentech Inc, South San Francisco, CA (R.T., J.A.E.); 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