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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Bone morphogenetic protein-9 inhibits lymphatic vessel formation via activin receptor-like kinase 1 during development and cancer progression</title><author><name sortKey="Yoshimatsu, Yasuhiro" sort="Yoshimatsu, Yasuhiro" uniqKey="Yoshimatsu Y" first="Yasuhiro" last="Yoshimatsu">Yasuhiro Yoshimatsu</name><affiliation><nlm:aff id="aff1">Department of Molecular Pathology, Graduate School of Medicine,<institution>The University of Tokyo</institution>, Bunkyo-ku, Tokyo 113-0033,<country>Japan</country>;</nlm:aff></affiliation></author><author><name sortKey="Lee, Yulia G" sort="Lee, Yulia G" uniqKey="Lee Y" first="Yulia G." last="Lee">Yulia G. Lee</name><affiliation><nlm:aff id="aff2">Laboratory for Vascular Biology and Stem Cell,<institution>Korea Advanced Institute of Science and Technology</institution>, Daejeon 305-701,<country>South Korea</country>;</nlm:aff></affiliation></author><author><name sortKey="Akatsu, Yuichi" sort="Akatsu, Yuichi" uniqKey="Akatsu Y" first="Yuichi" last="Akatsu">Yuichi Akatsu</name><affiliation><nlm:aff id="aff1">Department of Molecular Pathology, Graduate School of Medicine,<institution>The University of Tokyo</institution>, Bunkyo-ku, Tokyo 113-0033,<country>Japan</country>;</nlm:aff></affiliation></author><author><name sortKey="Taguchi, Luna" sort="Taguchi, Luna" uniqKey="Taguchi L" first="Luna" last="Taguchi">Luna Taguchi</name><affiliation><nlm:aff id="aff1">Department of Molecular Pathology, Graduate School of Medicine,<institution>The University of Tokyo</institution>, Bunkyo-ku, Tokyo 113-0033,<country>Japan</country>;</nlm:aff></affiliation></author><author><name sortKey="Suzuki, Hiroshi I" sort="Suzuki, Hiroshi I" uniqKey="Suzuki H" first="Hiroshi I." last="Suzuki">Hiroshi I. Suzuki</name><affiliation><nlm:aff id="aff1">Department of Molecular Pathology, Graduate School of Medicine,<institution>The University of Tokyo</institution>, Bunkyo-ku, Tokyo 113-0033,<country>Japan</country>;</nlm:aff></affiliation></author><author><name sortKey="Cunha, Sara I" sort="Cunha, Sara I" uniqKey="Cunha S" first="Sara I." last="Cunha">Sara I. Cunha</name><affiliation><nlm:aff id="aff3">Department of Medical Biochemistry and Biophysics, Division of Vascular Biology,<institution>Karolinska Institutet</institution>, SE-171 77 Stockholm,<country>Sweden</country>;</nlm:aff></affiliation></author><author><name sortKey="Maruyama, Kazuichi" sort="Maruyama, Kazuichi" uniqKey="Maruyama K" first="Kazuichi" last="Maruyama">Kazuichi Maruyama</name><affiliation><nlm:aff id="aff4">Department of Ophthalmology,<institution>Tohoku University Graduate School of Medicine</institution>, Sendai, Miyagi 980-8574,<country>Japan</country>;</nlm:aff></affiliation></author><author><name sortKey="Suzuki, Yuka" sort="Suzuki, Yuka" uniqKey="Suzuki Y" first="Yuka" last="Suzuki">Yuka Suzuki</name><affiliation><nlm:aff id="aff1">Department of Molecular Pathology, Graduate School of Medicine,<institution>The University of Tokyo</institution>, Bunkyo-ku, Tokyo 113-0033,<country>Japan</country>;</nlm:aff></affiliation></author><author><name sortKey="Yamazaki, Tomoko" sort="Yamazaki, Tomoko" uniqKey="Yamazaki T" first="Tomoko" last="Yamazaki">Tomoko Yamazaki</name><affiliation><nlm:aff id="aff1">Department of Molecular Pathology, Graduate School of Medicine,<institution>The University of Tokyo</institution>, Bunkyo-ku, Tokyo 113-0033,<country>Japan</country>;</nlm:aff></affiliation></author><author><name sortKey="Katsura, Akihiro" sort="Katsura, Akihiro" uniqKey="Katsura A" first="Akihiro" last="Katsura">Akihiro Katsura</name><affiliation><nlm:aff id="aff1">Department of Molecular Pathology, Graduate School of Medicine,<institution>The University of Tokyo</institution>, Bunkyo-ku, Tokyo 113-0033,<country>Japan</country>;</nlm:aff></affiliation></author><author><name sortKey="Oh, S Paul" sort="Oh, S Paul" uniqKey="Oh S" first="S. Paul" last="Oh">S. Paul Oh</name><affiliation><nlm:aff id="aff5">Department of Physiology and Functional Genomics, College of Medicine,<institution>University of Florida</institution>, Gainesville,<addr-line>FL</addr-line> 32610;</nlm:aff></affiliation></author><author><name sortKey="Zimmers, Teresa A" sort="Zimmers, Teresa A" uniqKey="Zimmers T" first="Teresa A." last="Zimmers">Teresa A. Zimmers</name><affiliation><nlm:aff id="aff6">Department of Cancer Biology and Surgery, Kimmel Cancer Center,<institution>Thomas Jefferson University</institution>, Philadelphia,<addr-line>PA 19107</addr-line>;</nlm:aff></affiliation></author><author><name sortKey="Lee, Se Jin" sort="Lee, Se Jin" uniqKey="Lee S" first="Se-Jin" last="Lee">Se-Jin Lee</name><affiliation><nlm:aff id="aff7">Department of Molecular Biology and Genetics,<institution>Johns Hopkins University School of Medicine</institution>, Baltimore,<addr-line>MD</addr-line> 21205;</nlm:aff></affiliation></author><author><name sortKey="Pietras, Kristian" sort="Pietras, Kristian" uniqKey="Pietras K" first="Kristian" last="Pietras">Kristian Pietras</name><affiliation><nlm:aff id="aff3">Department of Medical Biochemistry and Biophysics, Division of Vascular Biology,<institution>Karolinska Institutet</institution>, SE-171 77 Stockholm,<country>Sweden</country>;</nlm:aff></affiliation><affiliation><nlm:aff wicri:cut="; and" id="aff8">Department of Laboratory Medicine Lund,<institution>Lund University</institution>, Medicon Village, SE-223 81 Lund, Sweden</nlm:aff></affiliation></author><author><name sortKey="Koh, Gou Young" sort="Koh, Gou Young" uniqKey="Koh G" first="Gou Young" last="Koh">Gou Young Koh</name><affiliation><nlm:aff id="aff2">Laboratory for Vascular Biology and Stem Cell,<institution>Korea Advanced Institute of Science and Technology</institution>, Daejeon 305-701,<country>South Korea</country>;</nlm:aff></affiliation></author><author><name sortKey="Miyazono, Kohei" sort="Miyazono, Kohei" uniqKey="Miyazono K" first="Kohei" last="Miyazono">Kohei Miyazono</name><affiliation><nlm:aff id="aff1">Department of Molecular Pathology, Graduate School of Medicine,<institution>The University of Tokyo</institution>, Bunkyo-ku, Tokyo 113-0033,<country>Japan</country>;</nlm:aff></affiliation></author><author><name sortKey="Watabe, Tetsuro" sort="Watabe, Tetsuro" uniqKey="Watabe T" first="Tetsuro" last="Watabe">Tetsuro Watabe</name><affiliation><nlm:aff id="aff1">Department of Molecular Pathology, Graduate School of Medicine,<institution>The University of Tokyo</institution>, Bunkyo-ku, Tokyo 113-0033,<country>Japan</country>;</nlm:aff></affiliation><affiliation><nlm:aff id="aff9">Precursory Research for Embryonic Science and Technology (PRESTO),<country>Japan</country><institution>Science Technology Agency</institution>, Kawaguchi, Saitama 332-0012,<country>Japan</country></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">24133138</idno><idno type="pmc">3839734</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3839734</idno><idno type="RBID">PMC:3839734</idno><idno type="doi">10.1073/pnas.1310479110</idno><date when="2013">2013</date><idno type="wicri:Area/Pmc/Corpus">003170</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">003170</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Bone morphogenetic protein-9 inhibits lymphatic vessel formation via activin receptor-like kinase 1 during development and cancer progression</title><author><name sortKey="Yoshimatsu, Yasuhiro" sort="Yoshimatsu, Yasuhiro" uniqKey="Yoshimatsu Y" first="Yasuhiro" last="Yoshimatsu">Yasuhiro Yoshimatsu</name><affiliation><nlm:aff id="aff1">Department of Molecular Pathology, Graduate School of Medicine,<institution>The University of Tokyo</institution>, Bunkyo-ku, Tokyo 113-0033,<country>Japan</country>;</nlm:aff></affiliation></author><author><name sortKey="Lee, Yulia G" sort="Lee, Yulia G" uniqKey="Lee Y" first="Yulia G." last="Lee">Yulia G. Lee</name><affiliation><nlm:aff id="aff2">Laboratory for Vascular Biology and Stem Cell,<institution>Korea Advanced Institute of Science and Technology</institution>, Daejeon 305-701,<country>South Korea</country>;</nlm:aff></affiliation></author><author><name sortKey="Akatsu, Yuichi" sort="Akatsu, Yuichi" uniqKey="Akatsu Y" first="Yuichi" last="Akatsu">Yuichi Akatsu</name><affiliation><nlm:aff id="aff1">Department of Molecular Pathology, Graduate School of Medicine,<institution>The University of Tokyo</institution>, Bunkyo-ku, Tokyo 113-0033,<country>Japan</country>;</nlm:aff></affiliation></author><author><name sortKey="Taguchi, Luna" sort="Taguchi, Luna" uniqKey="Taguchi L" first="Luna" last="Taguchi">Luna Taguchi</name><affiliation><nlm:aff id="aff1">Department of Molecular Pathology, Graduate School of Medicine,<institution>The University of Tokyo</institution>, Bunkyo-ku, Tokyo 113-0033,<country>Japan</country>;</nlm:aff></affiliation></author><author><name sortKey="Suzuki, Hiroshi I" sort="Suzuki, Hiroshi I" uniqKey="Suzuki H" first="Hiroshi I." last="Suzuki">Hiroshi I. Suzuki</name><affiliation><nlm:aff id="aff1">Department of Molecular Pathology, Graduate School of Medicine,<institution>The University of Tokyo</institution>, Bunkyo-ku, Tokyo 113-0033,<country>Japan</country>;</nlm:aff></affiliation></author><author><name sortKey="Cunha, Sara I" sort="Cunha, Sara I" uniqKey="Cunha S" first="Sara I." last="Cunha">Sara I. Cunha</name><affiliation><nlm:aff id="aff3">Department of Medical Biochemistry and Biophysics, Division of Vascular Biology,<institution>Karolinska Institutet</institution>, SE-171 77 Stockholm,<country>Sweden</country>;</nlm:aff></affiliation></author><author><name sortKey="Maruyama, Kazuichi" sort="Maruyama, Kazuichi" uniqKey="Maruyama K" first="Kazuichi" last="Maruyama">Kazuichi Maruyama</name><affiliation><nlm:aff id="aff4">Department of Ophthalmology,<institution>Tohoku University Graduate School of Medicine</institution>, Sendai, Miyagi 980-8574,<country>Japan</country>;</nlm:aff></affiliation></author><author><name sortKey="Suzuki, Yuka" sort="Suzuki, Yuka" uniqKey="Suzuki Y" first="Yuka" last="Suzuki">Yuka Suzuki</name><affiliation><nlm:aff id="aff1">Department of Molecular Pathology, Graduate School of Medicine,<institution>The University of Tokyo</institution>, Bunkyo-ku, Tokyo 113-0033,<country>Japan</country>;</nlm:aff></affiliation></author><author><name sortKey="Yamazaki, Tomoko" sort="Yamazaki, Tomoko" uniqKey="Yamazaki T" first="Tomoko" last="Yamazaki">Tomoko Yamazaki</name><affiliation><nlm:aff id="aff1">Department of Molecular Pathology, Graduate School of Medicine,<institution>The University of Tokyo</institution>, Bunkyo-ku, Tokyo 113-0033,<country>Japan</country>;</nlm:aff></affiliation></author><author><name sortKey="Katsura, Akihiro" sort="Katsura, Akihiro" uniqKey="Katsura A" first="Akihiro" last="Katsura">Akihiro Katsura</name><affiliation><nlm:aff id="aff1">Department of Molecular Pathology, Graduate School of Medicine,<institution>The University of Tokyo</institution>, Bunkyo-ku, Tokyo 113-0033,<country>Japan</country>;</nlm:aff></affiliation></author><author><name sortKey="Oh, S Paul" sort="Oh, S Paul" uniqKey="Oh S" first="S. Paul" last="Oh">S. Paul Oh</name><affiliation><nlm:aff id="aff5">Department of Physiology and Functional Genomics, College of Medicine,<institution>University of Florida</institution>, Gainesville,<addr-line>FL</addr-line> 32610;</nlm:aff></affiliation></author><author><name sortKey="Zimmers, Teresa A" sort="Zimmers, Teresa A" uniqKey="Zimmers T" first="Teresa A." last="Zimmers">Teresa A. Zimmers</name><affiliation><nlm:aff id="aff6">Department of Cancer Biology and Surgery, Kimmel Cancer Center,<institution>Thomas Jefferson University</institution>, Philadelphia,<addr-line>PA 19107</addr-line>;</nlm:aff></affiliation></author><author><name sortKey="Lee, Se Jin" sort="Lee, Se Jin" uniqKey="Lee S" first="Se-Jin" last="Lee">Se-Jin Lee</name><affiliation><nlm:aff id="aff7">Department of Molecular Biology and Genetics,<institution>Johns Hopkins University School of Medicine</institution>, Baltimore,<addr-line>MD</addr-line> 21205;</nlm:aff></affiliation></author><author><name sortKey="Pietras, Kristian" sort="Pietras, Kristian" uniqKey="Pietras K" first="Kristian" last="Pietras">Kristian Pietras</name><affiliation><nlm:aff id="aff3">Department of Medical Biochemistry and Biophysics, Division of Vascular Biology,<institution>Karolinska Institutet</institution>, SE-171 77 Stockholm,<country>Sweden</country>;</nlm:aff></affiliation><affiliation><nlm:aff wicri:cut="; and" id="aff8">Department of Laboratory Medicine Lund,<institution>Lund University</institution>, Medicon Village, SE-223 81 Lund, Sweden</nlm:aff></affiliation></author><author><name sortKey="Koh, Gou Young" sort="Koh, Gou Young" uniqKey="Koh G" first="Gou Young" last="Koh">Gou Young Koh</name><affiliation><nlm:aff id="aff2">Laboratory for Vascular Biology and Stem Cell,<institution>Korea Advanced Institute of Science and Technology</institution>, Daejeon 305-701,<country>South Korea</country>;</nlm:aff></affiliation></author><author><name sortKey="Miyazono, Kohei" sort="Miyazono, Kohei" uniqKey="Miyazono K" first="Kohei" last="Miyazono">Kohei Miyazono</name><affiliation><nlm:aff id="aff1">Department of Molecular Pathology, Graduate School of Medicine,<institution>The University of Tokyo</institution>, Bunkyo-ku, Tokyo 113-0033,<country>Japan</country>;</nlm:aff></affiliation></author><author><name sortKey="Watabe, Tetsuro" sort="Watabe, Tetsuro" uniqKey="Watabe T" first="Tetsuro" last="Watabe">Tetsuro Watabe</name><affiliation><nlm:aff id="aff1">Department of Molecular Pathology, Graduate School of Medicine,<institution>The University of Tokyo</institution>, Bunkyo-ku, Tokyo 113-0033,<country>Japan</country>;</nlm:aff></affiliation><affiliation><nlm:aff id="aff9">Precursory Research for Embryonic Science and Technology (PRESTO),<country>Japan</country><institution>Science Technology Agency</institution>, Kawaguchi, Saitama 332-0012,<country>Japan</country></nlm:aff></affiliation></author></analytic><series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title><idno type="ISSN">0027-8424</idno><idno type="eISSN">1091-6490</idno><imprint><date when="2013">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Significance</title><p>Because lymphatic vessels (LVs) play critical roles not only in physiological processes such as maintenance of fluid homeostasis but also in pathological conditions including cancer metastasis, identification of factors that control LV formation is crucial. Signals mediated by activin receptor-like kinase 1 (ALK-1), a receptor for bone morphogenetic protein 9 (BMP-9), have been implicated in the formation of blood vessels because of its linkage to a human vascular disease. However, their roles in LV formation largely remain to be elucidated. Here, we show that BMP-9/ALK-1 signals inhibit LV formation in physiological and pathological conditions. Furthermore, we elucidated its molecular mechanisms in detail, using both in vivo and in vitro systems. These findings will help develop therapeutic strategies for LV-related diseases such as lymphedema and cancer.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Proc Natl Acad Sci U S A</journal-id><journal-id journal-id-type="iso-abbrev">Proc. Natl. Acad. Sci. U.S.A</journal-id><journal-id journal-id-type="hwp">pnas</journal-id><journal-id journal-id-type="pmc">pnas</journal-id><journal-id journal-id-type="publisher-id">PNAS</journal-id><journal-title-group><journal-title>Proceedings of the National Academy of Sciences of the United States of America</journal-title></journal-title-group><issn pub-type="ppub">0027-8424</issn><issn pub-type="epub">1091-6490</issn><publisher><publisher-name>National Academy of Sciences</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">24133138</article-id><article-id pub-id-type="pmc">3839734</article-id><article-id pub-id-type="publisher-id">201310479</article-id><article-id pub-id-type="doi">10.1073/pnas.1310479110</article-id><article-categories><subj-group subj-group-type="heading"><subject>Biological Sciences</subject><subj-group><subject>Cell Biology</subject></subj-group></subj-group></article-categories><title-group><article-title>Bone morphogenetic protein-9 inhibits lymphatic vessel formation via activin receptor-like kinase 1 during development and cancer progression</article-title><alt-title alt-title-type="short">BMP-9/ALK-1 signals inhibit lymphangiogenesis</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Yoshimatsu</surname><given-names>Yasuhiro</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lee</surname><given-names>Yulia G.</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Akatsu</surname><given-names>Yuichi</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Taguchi</surname><given-names>Luna</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Suzuki</surname><given-names>Hiroshi I.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Cunha</surname><given-names>Sara I.</given-names></name><xref ref-type="aff" rid="aff3"><sup>c</sup></xref></contrib><contrib contrib-type="author"><name><surname>Maruyama</surname><given-names>Kazuichi</given-names></name><xref ref-type="aff" rid="aff4"><sup>d</sup></xref></contrib><contrib contrib-type="author"><name><surname>Suzuki</surname><given-names>Yuka</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Yamazaki</surname><given-names>Tomoko</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Katsura</surname><given-names>Akihiro</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Oh</surname><given-names>S. Paul</given-names></name><xref ref-type="aff" rid="aff5"><sup>e</sup></xref></contrib><contrib contrib-type="author"><name><surname>Zimmers</surname><given-names>Teresa A.</given-names></name><xref ref-type="aff" rid="aff6"><sup>f</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lee</surname><given-names>Se-Jin</given-names></name><xref ref-type="aff" rid="aff7"><sup>g</sup></xref></contrib><contrib contrib-type="author"><name><surname>Pietras</surname><given-names>Kristian</given-names></name><xref ref-type="aff" rid="aff3"><sup>c</sup></xref><xref ref-type="aff" rid="aff8"><sup>h</sup></xref></contrib><contrib contrib-type="author"><name><surname>Koh</surname><given-names>Gou Young</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Miyazono</surname><given-names>Kohei</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="corresp" rid="cor1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Watabe</surname><given-names>Tetsuro</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="aff" rid="aff9"><sup>i</sup></xref><xref ref-type="author-notes" rid="fn2"><sup>2</sup></xref></contrib><aff id="aff1"><sup>a</sup>Department of Molecular Pathology, Graduate School of Medicine,<institution>The University of Tokyo</institution>, Bunkyo-ku, Tokyo 113-0033,<country>Japan</country>;</aff><aff id="aff2"><sup>b</sup>Laboratory for Vascular Biology and Stem Cell,<institution>Korea Advanced Institute of Science and Technology</institution>, Daejeon 305-701,<country>South Korea</country>;</aff><aff id="aff3"><sup>c</sup>Department of Medical Biochemistry and Biophysics, Division of Vascular Biology,<institution>Karolinska Institutet</institution>, SE-171 77 Stockholm,<country>Sweden</country>;</aff><aff id="aff4"><sup>d</sup>Department of Ophthalmology,<institution>Tohoku University Graduate School of Medicine</institution>, Sendai, Miyagi 980-8574,<country>Japan</country>;</aff><aff id="aff5"><sup>e</sup>Department of Physiology and Functional Genomics, College of Medicine,<institution>University of Florida</institution>, Gainesville,<addr-line>FL</addr-line> 32610;</aff><aff id="aff6"><sup>f</sup>Department of Cancer Biology and Surgery, Kimmel Cancer Center,<institution>Thomas Jefferson University</institution>, Philadelphia,<addr-line>PA 19107</addr-line>;</aff><aff id="aff7"><sup>g</sup>Department of Molecular Biology and Genetics,<institution>Johns Hopkins University School of Medicine</institution>, Baltimore,<addr-line>MD</addr-line> 21205;</aff><aff id="aff8"><sup>h</sup>Department of Laboratory Medicine Lund,<institution>Lund University</institution>, Medicon Village, SE-223 81 Lund, Sweden; and</aff><aff id="aff9"><sup>i</sup>Precursory Research for Embryonic Science and Technology (PRESTO),<country>Japan</country><institution>Science Technology Agency</institution>, Kawaguchi, Saitama 332-0012,<country>Japan</country></aff></contrib-group><author-notes><corresp id="cor1"><sup>1</sup>To whom correspondence should be addressed. E-mail: <email>miyazono@m.u-tokyo.ac.jp</email>.</corresp><fn fn-type="edited-by"><p>Edited<xref ref-type="fn" rid="fn1">*</xref> by Napoleone Ferrara, University of California, San Diego, La Jolla, CA, and approved September 20, 2013 (received for review June 18, 2013)</p></fn><fn fn-type="con"><p>Author contributions: Y.Y., K.P., G.Y.K., K. Miyazono, and T.W. designed research; Y.Y., Y.G.L., Y.A., L.T., S.I.C., K. Maruyama, Y.S., T.Y., and A.K. performed research; H.I.S., S.P.O., T.A.Z., S.-J.L., and G.Y.K. contributed new reagents/analytic tools; Y.Y., Y.G.L., Y.A., L.T., H.I.S., S.I.C., Y.S., K.P., G.Y.K., and T.W. analyzed data; and Y.Y., K.P., G.Y.K., K. Miyazono, and T.W. wrote the paper.</p></fn><fn fn-type="present-address" id="fn2"><p><sup>2</sup>Present address: Laboratory of Oncology, Department of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji-shi, Tokyo 192-0392, Japan.</p></fn></author-notes><pub-date pub-type="ppub"><day>19</day><month>11</month><year>2013</year></pub-date><pub-date pub-type="epub"><day>16</day><month>10</month><year>2013</year></pub-date><pub-date pub-type="pmc-release"><day>16</day><month>10</month><year>2013</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on the
<volume>110</volume><issue>47</issue><fpage>18940</fpage><lpage>18945</lpage><permissions><license license-type="open-access"><license-p>Freely available online through the PNAS open access option.</license-p></license></permissions><self-uri xlink:title="pdf" xlink:type="simple" xlink:href="pnas.201310479.pdf"></self-uri><abstract abstract-type="executive-summary"><title>Significance</title><p>Because lymphatic vessels (LVs) play critical roles not only in physiological processes such as maintenance of fluid homeostasis but also in pathological conditions including cancer metastasis, identification of factors that control LV formation is crucial. Signals mediated by activin receptor-like kinase 1 (ALK-1), a receptor for bone morphogenetic protein 9 (BMP-9), have been implicated in the formation of blood vessels because of its linkage to a human vascular disease. However, their roles in LV formation largely remain to be elucidated. Here, we show that BMP-9/ALK-1 signals inhibit LV formation in physiological and pathological conditions. Furthermore, we elucidated its molecular mechanisms in detail, using both in vivo and in vitro systems. These findings will help develop therapeutic strategies for LV-related diseases such as lymphedema and cancer.</p></abstract><abstract><p>Lymphatic vessels (LVs) play critical roles in the maintenance of fluid homeostasis and in pathological conditions, including cancer metastasis. Although mutations in <italic>ALK1</italic>, a member of the transforming growth factor (TGF)-β/bone morphogenetic protein (BMP) receptor family, have been linked to hereditary hemorrhagic telangiectasia, a human vascular disease, the roles of activin receptor-like kinase 1 (ALK-1) signals in LV formation largely remain to be elucidated. We show that ALK-1 signals inhibit LV formation, and LVs were enlarged in multiple organs in <italic>Alk1</italic>-depleted mice. These inhibitory effects of ALK-1 signaling were mediated by BMP-9, which decreased the number of cultured lymphatic endothelial cells. <italic>Bmp9</italic>-deficient mouse embryos consistently exhibited enlarged dermal LVs. BMP-9 also inhibited LV formation during inflammation and tumorigenesis. BMP-9 downregulated the expression of the transcription factor prospero-related homeobox 1, which is necessary to maintain lymphatic endothelial cell identity. Furthermore, silencing prospero-related homeobox 1 expression inhibited lymphatic endothelial cell proliferation. Our findings reveal a unique molecular basis for the physiological and pathological roles of BMP-9/ALK-1 signals in LV formation.</p></abstract><kwd-group><kwd>lymphangiogenesis</kwd><kwd>angiogenesis</kwd><kwd>blood vascular endothelial cells</kwd></kwd-group><counts><page-count count="6"></page-count></counts></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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