Alternatively spliced VEGF receptor-2 is an essential endogenous inhibitor of lymphatic vessels
Identifieur interne : 003824 ( Pmc/Checkpoint ); précédent : 003823; suivant : 003825Alternatively spliced VEGF receptor-2 is an essential endogenous inhibitor of lymphatic vessels
Auteurs : Romulo J. C. Albuquerque [États-Unis] ; Takahiko Hayashi [Japon] ; Won Gil Cho [États-Unis] ; Mark E. Kleinman [États-Unis] ; Sami Dridi [États-Unis] ; Atsunobu Takeda [États-Unis] ; Judit Z. Baffi [États-Unis] ; Kiyoshi Yamada [États-Unis] ; Hiroki Kaneko [États-Unis] ; Martha G. Green [États-Unis] ; Joe Chappell [États-Unis] ; Jörg Wilting [Allemagne] ; Herbert A. Weich [Allemagne] ; Satoru Yamagami [Japon] ; Shiro Amano [Japon] ; Nobuhisa Mizuki [Japon] ; Jonathan S. Alexander [États-Unis] ; Martha L. Peterson [États-Unis] ; Rolf A. Brekken [États-Unis] ; Masanori Hirashima [Japon] ; Seema Capoor [États-Unis] ; Tomohiko Usui [Japon] ; Balamurali K. Ambati [États-Unis] ; Jayakrishna Ambati [États-Unis]Source :
- Nature medicine [ 1078-8956 ] ; 2009.
Abstract
Disruption of the precise balance of positive and negative molecular regulators of blood and lymphatic vessels can lead to myriad diseases that affect one in four people worldwide. Although dozens of natural inhibitors of hemangiogenesis have been identified, an endogenous selective inhibitor of lymphatic vessels has not yet been described. We report the existence of a secreted, splice variant of vascular endothelial growth factor receptor-2 (sVegfr-2) that inhibits developmental and reparative lymphangiogenesis by blocking Vegf-c. Tissue-specific loss of sVegfr-2 in mice induced, at birth, spontaneous lymphatic invasion of the normally alymphatic cornea and hyperplasia of skin lymphatics without accompanying changes in blood vasculature. sVegfr-2 inhibited lymphangiogenesis but not hemangiogenesis induced by corneal suture injury or transplantation, enhanced corneal allograft survival, and suppressed lymphangioma cellular proliferation. Naturally occurring sVegfr-2 is a molecular uncoupler of blood and lymphatic vessels whose modulation might have a therapeutic role in lymphatic vascular malformations, transplantation, and potentially in tumor lymphangiogenesis and lymphedema.
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DOI: 10.1038/nm.2018
PubMed: 19668192
PubMed Central: 2882165
Affiliations:
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Albuquerque</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40536, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40536</wicri:regionArea><wicri:noRegion>Kentucky 40536</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="A2">Department of Physiology, University of Kentucky, Lexington, Kentucky 40536, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Physiology, University of Kentucky, Lexington, Kentucky 40536</wicri:regionArea><wicri:noRegion>Kentucky 40536</wicri:noRegion></affiliation></author><author><name sortKey="Hayashi, Takahiko" sort="Hayashi, Takahiko" uniqKey="Hayashi T" first="Takahiko" last="Hayashi">Takahiko Hayashi</name><affiliation wicri:level="1"><nlm:aff id="A3">Department of Ophthalmology, Yokohama City University, Yokohama, 221-0044, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Ophthalmology, Yokohama City University, Yokohama, 221-0044</wicri:regionArea><wicri:noRegion>221-0044</wicri:noRegion></affiliation></author><author><name sortKey="Cho, Won Gil" sort="Cho, Won Gil" uniqKey="Cho W" first="Won Gil" last="Cho">Won Gil Cho</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40536, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40536</wicri:regionArea><wicri:noRegion>Kentucky 40536</wicri:noRegion></affiliation></author><author><name sortKey="Kleinman, Mark E" sort="Kleinman, Mark E" uniqKey="Kleinman M" first="Mark E." last="Kleinman">Mark E. 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Baffi</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40536, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40536</wicri:regionArea><wicri:noRegion>Kentucky 40536</wicri:noRegion></affiliation></author><author><name sortKey="Yamada, Kiyoshi" sort="Yamada, Kiyoshi" uniqKey="Yamada K" first="Kiyoshi" last="Yamada">Kiyoshi Yamada</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40536, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40536</wicri:regionArea><wicri:noRegion>Kentucky 40536</wicri:noRegion></affiliation></author><author><name sortKey="Kaneko, Hiroki" sort="Kaneko, Hiroki" uniqKey="Kaneko H" first="Hiroki" last="Kaneko">Hiroki Kaneko</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40536, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40536</wicri:regionArea><wicri:noRegion>Kentucky 40536</wicri:noRegion></affiliation></author><author><name sortKey="Green, Martha G" sort="Green, Martha G" uniqKey="Green M" first="Martha G." last="Green">Martha G. Green</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40536, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40536</wicri:regionArea><wicri:noRegion>Kentucky 40536</wicri:noRegion></affiliation></author><author><name sortKey="Chappell, Joe" sort="Chappell, Joe" uniqKey="Chappell J" first="Joe" last="Chappell">Joe Chappell</name><affiliation wicri:level="1"><nlm:aff id="A4">Department of Plant & Soil Sciences, University of Kentucky, Lexington, Kentucky 40536, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Plant & Soil Sciences, University of Kentucky, Lexington, Kentucky 40536</wicri:regionArea><wicri:noRegion>Kentucky 40536</wicri:noRegion></affiliation></author><author><name sortKey="Wilting, Jorg" sort="Wilting, Jorg" uniqKey="Wilting J" first="Jörg" last="Wilting">Jörg Wilting</name><affiliation wicri:level="1"><nlm:aff id="A5">Department of Anatomy and Cell Biology, Georg-August-University, Goettingen, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Anatomy and Cell Biology, Georg-August-University, Goettingen</wicri:regionArea><wicri:noRegion>Goettingen</wicri:noRegion><wicri:noRegion>Goettingen</wicri:noRegion><wicri:noRegion>Goettingen</wicri:noRegion></affiliation></author><author><name sortKey="Weich, Herbert A" sort="Weich, Herbert A" uniqKey="Weich H" first="Herbert A." last="Weich">Herbert A. Weich</name><affiliation wicri:level="1"><nlm:aff id="A6">Department Gene Regulation and Differentiation, Helmholtz Centre for Infection Research, Braunschweig, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department Gene Regulation and Differentiation, Helmholtz Centre for Infection Research, Braunschweig</wicri:regionArea><wicri:noRegion>Braunschweig</wicri:noRegion><wicri:noRegion>Braunschweig</wicri:noRegion><wicri:noRegion>Braunschweig</wicri:noRegion></affiliation></author><author><name sortKey="Yamagami, Satoru" sort="Yamagami, Satoru" uniqKey="Yamagami S" first="Satoru" last="Yamagami">Satoru Yamagami</name><affiliation wicri:level="1"><nlm:aff id="A7">Department of Ophthalmology, University of Tokyo School of Medicine, Tokyo, 113-8655, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Ophthalmology, University of Tokyo School of Medicine, Tokyo, 113-8655</wicri:regionArea><wicri:noRegion>113-8655</wicri:noRegion></affiliation></author><author><name sortKey="Amano, Shiro" sort="Amano, Shiro" uniqKey="Amano S" first="Shiro" last="Amano">Shiro Amano</name><affiliation wicri:level="1"><nlm:aff id="A7">Department of Ophthalmology, University of Tokyo School of Medicine, Tokyo, 113-8655, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Ophthalmology, University of Tokyo School of Medicine, Tokyo, 113-8655</wicri:regionArea><wicri:noRegion>113-8655</wicri:noRegion></affiliation></author><author><name sortKey="Mizuki, Nobuhisa" sort="Mizuki, Nobuhisa" uniqKey="Mizuki N" first="Nobuhisa" last="Mizuki">Nobuhisa Mizuki</name><affiliation wicri:level="1"><nlm:aff id="A3">Department of Ophthalmology, Yokohama City University, Yokohama, 221-0044, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Ophthalmology, Yokohama City University, Yokohama, 221-0044</wicri:regionArea><wicri:noRegion>221-0044</wicri:noRegion></affiliation></author><author><name sortKey="Alexander, Jonathan S" sort="Alexander, Jonathan S" uniqKey="Alexander J" first="Jonathan S." last="Alexander">Jonathan S. Alexander</name><affiliation wicri:level="1"><nlm:aff id="A8">Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130-3932, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130-3932</wicri:regionArea><wicri:noRegion>Louisiana 71130-3932</wicri:noRegion></affiliation></author><author><name sortKey="Peterson, Martha L" sort="Peterson, Martha L" uniqKey="Peterson M" first="Martha L." last="Peterson">Martha L. Peterson</name><affiliation wicri:level="1"><nlm:aff id="A9">Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, Kentucky 40536, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, Kentucky 40536</wicri:regionArea><wicri:noRegion>Kentucky 40536</wicri:noRegion></affiliation></author><author><name sortKey="Brekken, Rolf A" sort="Brekken, Rolf A" uniqKey="Brekken R" first="Rolf A." last="Brekken">Rolf A. Brekken</name><affiliation wicri:level="1"><nlm:aff id="A10">Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8593, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8593</wicri:regionArea><wicri:noRegion>Texas 75390-8593</wicri:noRegion></affiliation></author><author><name sortKey="Hirashima, Masanori" sort="Hirashima, Masanori" uniqKey="Hirashima M" first="Masanori" last="Hirashima">Masanori Hirashima</name><affiliation wicri:level="1"><nlm:aff id="A11">Division of Vascular Biology, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Division of Vascular Biology, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe 650-0017</wicri:regionArea><wicri:noRegion>Kobe 650-0017</wicri:noRegion></affiliation></author><author><name sortKey="Capoor, Seema" sort="Capoor, Seema" uniqKey="Capoor S" first="Seema" last="Capoor">Seema Capoor</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40536, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40536</wicri:regionArea><wicri:noRegion>Kentucky 40536</wicri:noRegion></affiliation></author><author><name sortKey="Usui, Tomohiko" sort="Usui, Tomohiko" uniqKey="Usui T" first="Tomohiko" last="Usui">Tomohiko Usui</name><affiliation wicri:level="1"><nlm:aff id="A7">Department of Ophthalmology, University of Tokyo School of Medicine, Tokyo, 113-8655, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Ophthalmology, University of Tokyo School of Medicine, Tokyo, 113-8655</wicri:regionArea><wicri:noRegion>113-8655</wicri:noRegion></affiliation></author><author><name sortKey="Ambati, Balamurali K" sort="Ambati, Balamurali K" uniqKey="Ambati B" first="Balamurali K." last="Ambati">Balamurali K. Ambati</name><affiliation wicri:level="1"><nlm:aff id="A12">Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, Salt Lake City, Utah 84132</wicri:regionArea><wicri:noRegion>Utah 84132</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="A13">Department of Ophthalmology, Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, Utah 84148, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology, Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, Utah 84148</wicri:regionArea><wicri:noRegion>Utah 84148</wicri:noRegion></affiliation></author><author><name sortKey="Ambati, Jayakrishna" sort="Ambati, Jayakrishna" uniqKey="Ambati J" first="Jayakrishna" last="Ambati">Jayakrishna Ambati</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40536, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40536</wicri:regionArea><wicri:noRegion>Kentucky 40536</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="A2">Department of Physiology, University of Kentucky, Lexington, Kentucky 40536, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Physiology, University of Kentucky, Lexington, Kentucky 40536</wicri:regionArea><wicri:noRegion>Kentucky 40536</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">19668192</idno><idno type="pmc">2882165</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2882165</idno><idno type="RBID">PMC:2882165</idno><idno type="doi">10.1038/nm.2018</idno><date when="2009">2009</date><idno type="wicri:Area/Pmc/Corpus">004712</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">004712</idno><idno type="wicri:Area/Pmc/Curation">004711</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">004711</idno><idno type="wicri:Area/Pmc/Checkpoint">003824</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">003824</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Alternatively spliced VEGF receptor-2 is an essential endogenous inhibitor of lymphatic vessels</title><author><name sortKey="Albuquerque, Romulo J C" sort="Albuquerque, Romulo J C" uniqKey="Albuquerque R" first="Romulo J. C." last="Albuquerque">Romulo J. C. Albuquerque</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40536, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40536</wicri:regionArea><wicri:noRegion>Kentucky 40536</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="A2">Department of Physiology, University of Kentucky, Lexington, Kentucky 40536, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Physiology, University of Kentucky, Lexington, Kentucky 40536</wicri:regionArea><wicri:noRegion>Kentucky 40536</wicri:noRegion></affiliation></author><author><name sortKey="Hayashi, Takahiko" sort="Hayashi, Takahiko" uniqKey="Hayashi T" first="Takahiko" last="Hayashi">Takahiko Hayashi</name><affiliation wicri:level="1"><nlm:aff id="A3">Department of Ophthalmology, Yokohama City University, Yokohama, 221-0044, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Ophthalmology, Yokohama City University, Yokohama, 221-0044</wicri:regionArea><wicri:noRegion>221-0044</wicri:noRegion></affiliation></author><author><name sortKey="Cho, Won Gil" sort="Cho, Won Gil" uniqKey="Cho W" first="Won Gil" last="Cho">Won Gil Cho</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40536, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40536</wicri:regionArea><wicri:noRegion>Kentucky 40536</wicri:noRegion></affiliation></author><author><name sortKey="Kleinman, Mark E" sort="Kleinman, Mark E" uniqKey="Kleinman M" first="Mark E." last="Kleinman">Mark E. Kleinman</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40536, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40536</wicri:regionArea><wicri:noRegion>Kentucky 40536</wicri:noRegion></affiliation></author><author><name sortKey="Dridi, Sami" sort="Dridi, Sami" uniqKey="Dridi S" first="Sami" last="Dridi">Sami Dridi</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40536, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40536</wicri:regionArea><wicri:noRegion>Kentucky 40536</wicri:noRegion></affiliation></author><author><name sortKey="Takeda, Atsunobu" sort="Takeda, Atsunobu" uniqKey="Takeda A" first="Atsunobu" last="Takeda">Atsunobu Takeda</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40536, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40536</wicri:regionArea><wicri:noRegion>Kentucky 40536</wicri:noRegion></affiliation></author><author><name sortKey="Baffi, Judit Z" sort="Baffi, Judit Z" uniqKey="Baffi J" first="Judit Z." last="Baffi">Judit Z. Baffi</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40536, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40536</wicri:regionArea><wicri:noRegion>Kentucky 40536</wicri:noRegion></affiliation></author><author><name sortKey="Yamada, Kiyoshi" sort="Yamada, Kiyoshi" uniqKey="Yamada K" first="Kiyoshi" last="Yamada">Kiyoshi Yamada</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40536, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40536</wicri:regionArea><wicri:noRegion>Kentucky 40536</wicri:noRegion></affiliation></author><author><name sortKey="Kaneko, Hiroki" sort="Kaneko, Hiroki" uniqKey="Kaneko H" first="Hiroki" last="Kaneko">Hiroki Kaneko</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40536, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40536</wicri:regionArea><wicri:noRegion>Kentucky 40536</wicri:noRegion></affiliation></author><author><name sortKey="Green, Martha G" sort="Green, Martha G" uniqKey="Green M" first="Martha G." last="Green">Martha G. Green</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40536, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40536</wicri:regionArea><wicri:noRegion>Kentucky 40536</wicri:noRegion></affiliation></author><author><name sortKey="Chappell, Joe" sort="Chappell, Joe" uniqKey="Chappell J" first="Joe" last="Chappell">Joe Chappell</name><affiliation wicri:level="1"><nlm:aff id="A4">Department of Plant & Soil Sciences, University of Kentucky, Lexington, Kentucky 40536, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Plant & Soil Sciences, University of Kentucky, Lexington, Kentucky 40536</wicri:regionArea><wicri:noRegion>Kentucky 40536</wicri:noRegion></affiliation></author><author><name sortKey="Wilting, Jorg" sort="Wilting, Jorg" uniqKey="Wilting J" first="Jörg" last="Wilting">Jörg Wilting</name><affiliation wicri:level="1"><nlm:aff id="A5">Department of Anatomy and Cell Biology, Georg-August-University, Goettingen, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Anatomy and Cell Biology, Georg-August-University, Goettingen</wicri:regionArea><wicri:noRegion>Goettingen</wicri:noRegion><wicri:noRegion>Goettingen</wicri:noRegion><wicri:noRegion>Goettingen</wicri:noRegion></affiliation></author><author><name sortKey="Weich, Herbert A" sort="Weich, Herbert A" uniqKey="Weich H" first="Herbert A." last="Weich">Herbert A. Weich</name><affiliation wicri:level="1"><nlm:aff id="A6">Department Gene Regulation and Differentiation, Helmholtz Centre for Infection Research, Braunschweig, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department Gene Regulation and Differentiation, Helmholtz Centre for Infection Research, Braunschweig</wicri:regionArea><wicri:noRegion>Braunschweig</wicri:noRegion><wicri:noRegion>Braunschweig</wicri:noRegion><wicri:noRegion>Braunschweig</wicri:noRegion></affiliation></author><author><name sortKey="Yamagami, Satoru" sort="Yamagami, Satoru" uniqKey="Yamagami S" first="Satoru" last="Yamagami">Satoru Yamagami</name><affiliation wicri:level="1"><nlm:aff id="A7">Department of Ophthalmology, University of Tokyo School of Medicine, Tokyo, 113-8655, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Ophthalmology, University of Tokyo School of Medicine, Tokyo, 113-8655</wicri:regionArea><wicri:noRegion>113-8655</wicri:noRegion></affiliation></author><author><name sortKey="Amano, Shiro" sort="Amano, Shiro" uniqKey="Amano S" first="Shiro" last="Amano">Shiro Amano</name><affiliation wicri:level="1"><nlm:aff id="A7">Department of Ophthalmology, University of Tokyo School of Medicine, Tokyo, 113-8655, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Ophthalmology, University of Tokyo School of Medicine, Tokyo, 113-8655</wicri:regionArea><wicri:noRegion>113-8655</wicri:noRegion></affiliation></author><author><name sortKey="Mizuki, Nobuhisa" sort="Mizuki, Nobuhisa" uniqKey="Mizuki N" first="Nobuhisa" last="Mizuki">Nobuhisa Mizuki</name><affiliation wicri:level="1"><nlm:aff id="A3">Department of Ophthalmology, Yokohama City University, Yokohama, 221-0044, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Ophthalmology, Yokohama City University, Yokohama, 221-0044</wicri:regionArea><wicri:noRegion>221-0044</wicri:noRegion></affiliation></author><author><name sortKey="Alexander, Jonathan S" sort="Alexander, Jonathan S" uniqKey="Alexander J" first="Jonathan S." last="Alexander">Jonathan S. Alexander</name><affiliation wicri:level="1"><nlm:aff id="A8">Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130-3932, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130-3932</wicri:regionArea><wicri:noRegion>Louisiana 71130-3932</wicri:noRegion></affiliation></author><author><name sortKey="Peterson, Martha L" sort="Peterson, Martha L" uniqKey="Peterson M" first="Martha L." last="Peterson">Martha L. Peterson</name><affiliation wicri:level="1"><nlm:aff id="A9">Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, Kentucky 40536, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, Kentucky 40536</wicri:regionArea><wicri:noRegion>Kentucky 40536</wicri:noRegion></affiliation></author><author><name sortKey="Brekken, Rolf A" sort="Brekken, Rolf A" uniqKey="Brekken R" first="Rolf A." last="Brekken">Rolf A. Brekken</name><affiliation wicri:level="1"><nlm:aff id="A10">Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8593, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8593</wicri:regionArea><wicri:noRegion>Texas 75390-8593</wicri:noRegion></affiliation></author><author><name sortKey="Hirashima, Masanori" sort="Hirashima, Masanori" uniqKey="Hirashima M" first="Masanori" last="Hirashima">Masanori Hirashima</name><affiliation wicri:level="1"><nlm:aff id="A11">Division of Vascular Biology, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Division of Vascular Biology, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe 650-0017</wicri:regionArea><wicri:noRegion>Kobe 650-0017</wicri:noRegion></affiliation></author><author><name sortKey="Capoor, Seema" sort="Capoor, Seema" uniqKey="Capoor S" first="Seema" last="Capoor">Seema Capoor</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40536, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40536</wicri:regionArea><wicri:noRegion>Kentucky 40536</wicri:noRegion></affiliation></author><author><name sortKey="Usui, Tomohiko" sort="Usui, Tomohiko" uniqKey="Usui T" first="Tomohiko" last="Usui">Tomohiko Usui</name><affiliation wicri:level="1"><nlm:aff id="A7">Department of Ophthalmology, University of Tokyo School of Medicine, Tokyo, 113-8655, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Ophthalmology, University of Tokyo School of Medicine, Tokyo, 113-8655</wicri:regionArea><wicri:noRegion>113-8655</wicri:noRegion></affiliation></author><author><name sortKey="Ambati, Balamurali K" sort="Ambati, Balamurali K" uniqKey="Ambati B" first="Balamurali K." last="Ambati">Balamurali K. Ambati</name><affiliation wicri:level="1"><nlm:aff id="A12">Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, Salt Lake City, Utah 84132</wicri:regionArea><wicri:noRegion>Utah 84132</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="A13">Department of Ophthalmology, Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, Utah 84148, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology, Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, Utah 84148</wicri:regionArea><wicri:noRegion>Utah 84148</wicri:noRegion></affiliation></author><author><name sortKey="Ambati, Jayakrishna" sort="Ambati, Jayakrishna" uniqKey="Ambati J" first="Jayakrishna" last="Ambati">Jayakrishna Ambati</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40536, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40536</wicri:regionArea><wicri:noRegion>Kentucky 40536</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="A2">Department of Physiology, University of Kentucky, Lexington, Kentucky 40536, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Physiology, University of Kentucky, Lexington, Kentucky 40536</wicri:regionArea><wicri:noRegion>Kentucky 40536</wicri:noRegion></affiliation></author></analytic><series><title level="j">Nature medicine</title><idno type="ISSN">1078-8956</idno><idno type="eISSN">1546-170X</idno><imprint><date when="2009">2009</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="P2">Disruption of the precise balance of positive and negative molecular regulators of blood and lymphatic vessels can lead to myriad diseases that affect one in four people worldwide. Although dozens of natural inhibitors of hemangiogenesis have been identified, an endogenous selective inhibitor of lymphatic vessels has not yet been described. We report the existence of a secreted, splice variant of vascular endothelial growth factor receptor-2 (sVegfr-2) that inhibits developmental and reparative lymphangiogenesis by blocking Vegf-c. Tissue-specific loss of sVegfr-2 in mice induced, at birth, spontaneous lymphatic invasion of the normally alymphatic cornea and hyperplasia of skin lymphatics without accompanying changes in blood vasculature. sVegfr-2 inhibited lymphangiogenesis but not hemangiogenesis induced by corneal suture injury or transplantation, enhanced corneal allograft survival, and suppressed lymphangioma cellular proliferation. Naturally occurring sVegfr-2 is a molecular uncoupler of blood and lymphatic vessels whose modulation might have a therapeutic role in lymphatic vascular malformations, transplantation, and potentially in tumor lymphangiogenesis and lymphedema.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Ferrara, N" uniqKey="Ferrara N">N Ferrara</name></author><author><name sortKey="Kerbel, Rs" uniqKey="Kerbel R">RS Kerbel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Carmeliet, P" uniqKey="Carmeliet P">P Carmeliet</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fenwick, A" uniqKey="Fenwick A">A Fenwick</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Carmeliet, P" uniqKey="Carmeliet P">P Carmeliet</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ferrara, N" uniqKey="Ferrara N">N 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<front><journal-meta><journal-id journal-id-type="nlm-journal-id">9502015</journal-id><journal-id journal-id-type="pubmed-jr-id">8791</journal-id><journal-id journal-id-type="nlm-ta">Nat Med</journal-id><journal-id journal-id-type="iso-abbrev">Nat. Med.</journal-id><journal-title-group><journal-title>Nature medicine</journal-title></journal-title-group><issn pub-type="ppub">1078-8956</issn><issn pub-type="epub">1546-170X</issn></journal-meta><article-meta><article-id pub-id-type="pmid">19668192</article-id><article-id pub-id-type="pmc">2882165</article-id><article-id pub-id-type="doi">10.1038/nm.2018</article-id><article-id pub-id-type="manuscript">NIHMS131529</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Alternatively spliced VEGF receptor-2 is an essential endogenous inhibitor of lymphatic vessels</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Albuquerque</surname><given-names>Romulo J.C.</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Hayashi</surname><given-names>Takahiko</given-names></name><xref ref-type="aff" rid="A3">3</xref><xref ref-type="author-notes" rid="FN1">14</xref></contrib><contrib contrib-type="author"><name><surname>Cho</surname><given-names>Won Gil</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="author-notes" rid="FN1">14</xref></contrib><contrib contrib-type="author"><name><surname>Kleinman</surname><given-names>Mark E.</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="author-notes" rid="FN1">14</xref></contrib><contrib contrib-type="author"><name><surname>Dridi</surname><given-names>Sami</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Takeda</surname><given-names>Atsunobu</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Baffi</surname><given-names>Judit Z.</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Yamada</surname><given-names>Kiyoshi</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Kaneko</surname><given-names>Hiroki</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Green</surname><given-names>Martha G.</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Chappell</surname><given-names>Joe</given-names></name><xref ref-type="aff" rid="A4">4</xref></contrib><contrib contrib-type="author"><name><surname>Wilting</surname><given-names>Jörg</given-names></name><xref ref-type="aff" rid="A5">5</xref></contrib><contrib contrib-type="author"><name><surname>Weich</surname><given-names>Herbert A.</given-names></name><xref ref-type="aff" rid="A6">6</xref></contrib><contrib contrib-type="author"><name><surname>Yamagami</surname><given-names>Satoru</given-names></name><xref ref-type="aff" rid="A7">7</xref></contrib><contrib contrib-type="author"><name><surname>Amano</surname><given-names>Shiro</given-names></name><xref ref-type="aff" rid="A7">7</xref></contrib><contrib contrib-type="author"><name><surname>Mizuki</surname><given-names>Nobuhisa</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Alexander</surname><given-names>Jonathan S.</given-names></name><xref ref-type="aff" rid="A8">8</xref></contrib><contrib contrib-type="author"><name><surname>Peterson</surname><given-names>Martha L.</given-names></name><xref ref-type="aff" rid="A9">9</xref></contrib><contrib contrib-type="author"><name><surname>Brekken</surname><given-names>Rolf A.</given-names></name><xref ref-type="aff" rid="A10">10</xref></contrib><contrib contrib-type="author"><name><surname>Hirashima</surname><given-names>Masanori</given-names></name><xref ref-type="aff" rid="A11">11</xref></contrib><contrib contrib-type="author"><name><surname>Capoor</surname><given-names>Seema</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Usui</surname><given-names>Tomohiko</given-names></name><xref ref-type="aff" rid="A7">7</xref></contrib><contrib contrib-type="author"><name><surname>Ambati</surname><given-names>Balamurali K.</given-names></name><xref ref-type="aff" rid="A12">12</xref><xref ref-type="aff" rid="A13">13</xref></contrib><contrib contrib-type="author"><name><surname>Ambati</surname><given-names>Jayakrishna</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref></contrib></contrib-group><aff id="A1"><label>1</label>Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40536, USA</aff><aff id="A2"><label>2</label>Department of Physiology, University of Kentucky, Lexington, Kentucky 40536, USA</aff><aff id="A3"><label>3</label>Department of Ophthalmology, Yokohama City University, Yokohama, 221-0044, Japan</aff><aff id="A4"><label>4</label>Department of Plant & Soil Sciences, University of Kentucky, Lexington, Kentucky 40536, USA</aff><aff id="A5"><label>5</label>Department of Anatomy and Cell Biology, Georg-August-University, Goettingen, Germany</aff><aff id="A6"><label>6</label>Department Gene Regulation and Differentiation, Helmholtz Centre for Infection Research, Braunschweig, Germany</aff><aff id="A7"><label>7</label>Department of Ophthalmology, University of Tokyo School of Medicine, Tokyo, 113-8655, Japan</aff><aff id="A8"><label>8</label>Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130-3932, USA</aff><aff id="A9"><label>9</label>Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, Kentucky 40536, USA</aff><aff id="A10"><label>10</label>Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8593, USA</aff><aff id="A11"><label>11</label>Division of Vascular Biology, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan</aff><aff id="A12"><label>12</label>Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA</aff><aff id="A13"><label>13</label>Department of Ophthalmology, Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, Utah 84148, USA</aff><author-notes><fn fn-type="equal" id="FN1"><label>14</label><p id="P1">These authors contributed equally to this work.</p></fn><corresp id="CR1">Correspondence should be addressed to J.A. (<email>jamba2@email.uky.edu</email>).</corresp></author-notes><pub-date pub-type="nihms-submitted"><day>14</day><month>5</month><year>2010</year></pub-date><pub-date pub-type="epub"><day>09</day><month>8</month><year>2009</year></pub-date><pub-date pub-type="ppub"><month>9</month><year>2009</year></pub-date><pub-date pub-type="pmc-release"><day>08</day><month>6</month><year>2010</year></pub-date><volume>15</volume><issue>9</issue><fpage>1023</fpage><lpage>1030</lpage><pmc-comment>elocation-id from pubmed: 10.1038/nm.2018</pmc-comment>
<permissions><license xlink:href="http://www.nature.com/authors/editorial_policies/license.html#terms"><license-p>Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:<ext-link ext-link-type="uri" xlink:href="http://www.nature.com/authors/editorial_policies/license.html#terms">http://www.nature.com/authors/editorial_policies/license.html#terms</ext-link></license-p></license></permissions><abstract><p id="P2">Disruption of the precise balance of positive and negative molecular regulators of blood and lymphatic vessels can lead to myriad diseases that affect one in four people worldwide. Although dozens of natural inhibitors of hemangiogenesis have been identified, an endogenous selective inhibitor of lymphatic vessels has not yet been described. We report the existence of a secreted, splice variant of vascular endothelial growth factor receptor-2 (sVegfr-2) that inhibits developmental and reparative lymphangiogenesis by blocking Vegf-c. Tissue-specific loss of sVegfr-2 in mice induced, at birth, spontaneous lymphatic invasion of the normally alymphatic cornea and hyperplasia of skin lymphatics without accompanying changes in blood vasculature. sVegfr-2 inhibited lymphangiogenesis but not hemangiogenesis induced by corneal suture injury or transplantation, enhanced corneal allograft survival, and suppressed lymphangioma cellular proliferation. Naturally occurring sVegfr-2 is a molecular uncoupler of blood and lymphatic vessels whose modulation might have a therapeutic role in lymphatic vascular malformations, transplantation, and potentially in tumor lymphangiogenesis and lymphedema.</p></abstract></article-meta></front><floats-group><fig id="F1" position="float"><label>Figure 1</label><caption><p>Loss of endogenous sVegfr-2, which antagonizes Vegf-c, leads to spontaneous corneal lymphangiogenesis. <bold>(a) </bold><italic>sVegfr2</italic> mRNA detection (purple-blue) by <italic>in situ</italic> hybridization in the mouse cornea. Epi, epithelium; Str, stroma. (<bold>b)</bold> sVegfr-2 immunolocalization (brown) in the mouse cornea using AA21127. Cell nuclei stained blue by hematoxylin. (<bold>c)</bold> Representative corneal flat mounts of a <italic>LeCre/Vegfr2<sup>loxP/loxP</sup></italic> mouse (<italic>n</italic> = 30). Lyve-1<sup>+</sup> (green) lymphatic and Cd31<sup>+</sup> (red) Lyve-1<sup>–</sup> blood vessels are shown. (<bold>d,e)</bold> Immunofluorescent detection of Lyve-1<sup>+</sup> (green) Prox1<sup>+</sup> (red) lymphatic vessels in corneal whole mounts (<bold>d</bold>) and cross sections (<bold>e</bold>) of <italic>LeCre/Vegfr2<sup>loxP/loxP</sup></italic> mice. <bold>(f)</bold> Transmission electron microscopy of lymphatic vessel in cornea of <italic>LeCre/Vegfr2<sup>loxP/loxP</sup></italic> mice. Inset (right). (<bold>g</bold>) Quantification of vessel area in corneal flat mounts (<italic>n</italic> = 20). Error bars depict s.e.m. <bold>(h)</bold> Representative western blot of samples of recombinant sVegfr-2 (rsVegfr-2) incubated with recombinant Vegf-c (rVegf-c) and immunoprecipitated with either anti-Vegfr-2 (3<sup>rd</sup> lane from the left) antibody or isotype control IgG (4<sup>th</sup> lane from the left) and immunoblotted with anti-Vegf-c antibody. sVegfr-2 and Vegf-c resolution shown on first two lanes from the left. <bold>(i)</bold> Representative immunoblot of Vegf-c-induced Vegfr-3 phosphorylation of mouse lymphatic endothelial cells. Vegfr-3 re-blot is shown. ϕ, media only. <bold>(j)</bold> Proliferation of human lymphatic microvascular endothelial cells, quantified by BrdU uptake. (<bold>f,j)</bold>, NS, not significant ;* <italic>P</italic> < 0.05, Significance by Mann Whitney U test. Error bars depict s.e.m. Scale bars: (<bold>a,b,d</bold>), 50 μm; (<bold>c</bold>) 500 μm; (<bold>e</bold>) 25 μm; left panel of (<bold>g</bold>), 1 μm; right panel of (<bold>g</bold>), 200 nm.</p></caption><graphic xlink:href="nihms-131529-f0001"></graphic></fig><fig id="F2" position="float"><label>Figure 2</label><caption><p>sVegfr-2 inhibits reparative corneal lymphangiogenesis and rejection of corneal allografts. <bold>(a)</bold> Representative western blot, 5 days after suture placement in <italic>Vegfr2<sup>loxP/loxP</sup></italic> mouse corneas treated with plasmid coding for Cre recombinase (pCre) or empty vector (pNull) (<italic>n</italic> = 8). Loading control, Gapdh. Bottom panel (arrows) shows Lyve-1<sup>+</sup> vessels-green 14 days after suture placement. <bold>(b)</bold> Real-time PCR of <italic>sVegfr2</italic> in the <italic>Vegfr2<sup>loxP/loxP</sup></italic> mouse corneas (<italic>n</italic> = 4). <bold>(c)</bold> Quantification of vessel area in corneal flat mounts of <italic>Vegfr2<sup>loxP/loxP</sup></italic> and Balb/C wild-type (WT) corneas (<italic>n</italic> = 5-6) and <italic>Vegfr2<sup>loxP/loxP</sup></italic> mice corneas injected with pCre followed by systemic administration of a Vegfr-3 tyrosine kinase inhibitor (R3TKI) (<italic>n</italic> = 8<italic>)</italic>. Lyve-1<sup>+</sup>, lymphatic vessel - white bars; Cd31<sup>+</sup>/Lyve-1<sup>–</sup>, blood vessel – black bars. <bold>(d)</bold> Representative corneal flat mounts of C57Bl/6J wild-type mouse corneas. Lyve-1<sup>+</sup>, lymphatic vessel - green;Cd31<sup>+</sup>/Lyve-1<sup>–</sup>, blood vessel – red. <bold>(e)</bold> Quantification of vessel area in flat mounts of C57Bl/6J wild-type mouse corneas (<italic>n</italic> = 5). Lyve-1<sup>+</sup>, lymphatic vessel - white bars; Cd31<sup>+</sup>/Lyve-1<sup>–</sup>, blood vessel – black bars. <bold>(f)</bold> Kaplan-Meier survival curves showing survival of corneal grafts in BALB/c hosts (<italic>n</italic> = 10–13). <bold>(g)</bold> Representative corneal flat mounts of transplanted mouse corneas. Lyve-1<sup>+</sup>, lymphatic vessel - green;Cd31<sup>+</sup>/Lyve-1<sup>–</sup>, blood vessel – red. Limbus, bottom dotted-line; Recipient-donor interface, top dotted-line. <bold>(h)</bold> Quantification of corneal graft vessel area in flat mounts of transplants (<italic>n</italic> = 5). Lyve-1<sup>+</sup>, lymphatic vessel - white bars;Cd31<sup>+</sup>/Lyve-1<sup>–</sup>, blood vessel – black bars. (NS, non-significant; *, <italic>P</italic> < 0.05; Significance by Mann Whitney U test). Error bars depict s.e.m. Scale bars: (<bold>a,d,g</bold>), 500 μm.</p></caption><graphic xlink:href="nihms-131529-f0002"></graphic></fig><fig id="F3" position="float"><label>Figure 3</label><caption><p>Endogenous Vegf-c and sVegfr-2 selectively modulate corneal lymphangiogenesis. <bold>(a)</bold> Representative color photographs of sutured wild-type mouse corneas (top). Representative flat mounts of sutured corneas. Lyve-1<sup>+</sup>, lymphatic vessel - green;Cd31<sup>+</sup>/Lyve-1<sup>–</sup>, blood vessel – red. <bold>(b)</bold> Quantification of corneal vessel area of sutured corneas of wild-type mice (<italic>n</italic> = 8). Lyve-1<sup>+</sup>, lymphatic vessel - white bars; Cd31<sup>+</sup>/Lyve-1<sup>–</sup>, blood vessel – black bars. <bold>(c)</bold> ELISA quantification of Vegf-c/VEGF-C in wild-type mouse corneas 2 and 4 days after suture placement or implantation of pellets containing 160 ng recombinant human VEGF-C. <bold>(d)</bold> Immunobloting of sVegfr-2 secreted by transfected human embryonic kidney cells (HEK), Chinese hamster ovary cells (CHO), and mouse corneal epithelial cells (KEPI) under reducing (RED) and non-reducing (NR) conditions. M, marker; lane 1. pNull; lane 2. psVegfr-2 (RED); lane 3. psVegfr-2 (NR). <bold>(e)</bold> Silver staining of polyacrylamide gel loaded with Vegfr-2/Fc and recombinant sVegfr-2 (rsVegfr-2) and resolved under reducing versus non-reducing conditions. Dim, dimer; Mon, monomer; M, marker. <bold>(f)</bold> Corneal area occupied by blood vessels (Cd31<sup>+</sup>/Lyve-1<sup>–</sup>) following suture injury in wild-type mice. <bold>(g)</bold> Representative immunoblot of phosphorylated Vegfr-2 (phosVegfr-2) of porcine aortic endothelial cells stably transfected with Vegfr-2 (PAE-KDR). Reblotting for total Vegfr-2 and Vinculin are shown. ϕ, no Vegf-a. <bold>(h)</bold> Corneal area occupied by blood vessels (Cd31<sup>+</sup>/Lyve-1<sup>–</sup>) following pVegf-a injection. NS, not significant; *, <italic>P</italic> < 0.05; Significance by Mann Whitney U test. n = 4–8. Error bars depict s.e.m.(<bold>b,c,f,h</bold>). Scale bar: (<bold>a</bold>), 500μm.</p></caption><graphic xlink:href="nihms-131529-f0003"></graphic></fig><fig id="F4" position="float"><label>Figure 4</label><caption><p>Loss of <italic>sVegfr2</italic> in the skin induces lymphatic hyperplasia. <bold>(a) </bold><italic>sVegfr2</italic> mRNA detection (purple-blue) by <italic>in situ</italic> hybridization in the mouse skin. (<bold>b)</bold> sVegfr-2 immunolocalization (brown) in the mouse skin using AA21127. Cell nuclei stained blue by hematoxylin. (<bold>c)</bold> Immunofluorescence of sVegfr-2 in the skin of newborn mice. Superficial keratin autofluorescence is seen in all instances. Cell nuclei stained with DAPI. Scale bar, 50 μm. <bold>(d)</bold> Representative whole mount of the ventral skin of P0 mice. Lyve-1<sup>+</sup> (green) lymphatic and Cd31<sup>+</sup> (red) Lyve-1<sup>–</sup> blood vessels are shown. <bold>(e)</bold> Skin area occupied by blood vessels (Cd31<sup>+</sup>/Lyve-1<sup>–</sup>, black bars) and lymphatic vessels (Lyve-1<sup>+</sup>, white bars) in P0 mice. <bold>(f)</bold> Representative whole mount immunofluorescent image showing Lyve-1<sup>+</sup> (green) and Prox1<sup>+</sup> (red) lymphatic vessels of P0 mice (<italic>n</italic> = 14). <bold>(g)</bold> Lymphatic endothelial cell (LEC) density, quantified by number of Prox1<sup>+</sup> (red) nuclei per 100 μm of lymphatic vessel (Lyve-1<sup>+</sup>, green) length, in P0 mice (<italic>n</italic> = 12). <bold>(h)</bold> Quantitative branch point analysis of Lyve-1<sup>+</sup> lymphatic vessels per unit area (750 μm × 750 μm) is shown (<italic>n</italic> = 8). Scale bar<bold>: (a-d,f)</bold>, 50 μm; (<bold>e,g,h</bold>) NS, not significant; *, <italic>P</italic> < 0.05; Significance by Mann Whitney U test. Error bars depict s.e.m.</p></caption><graphic xlink:href="nihms-131529-f0004"></graphic></fig><fig id="F5" position="float"><label>Figure 5</label><caption><p>sVegfr-2 is produced by blood endothelial cells (BECs) and skin epithelium and circulates in plasma. (<bold>a</bold>) Representative western blots of mouse plasma immunoprecipitated with an antibody against the amino terminus of Vegfr-2 (N) and immunoblotted with either anti-Vegfr-2 (N; left), anti-sVegfr-2 (C; right) and an antibody against the carboxyl terminus of mbVegfr-2 (C; center). (b) PCR amplification of <italic>sVegfr2</italic> mRNA using cDNA derived from mouse lymphatic endothelial cells (LECs) and mouse BECs isolated from the brain (Bend3), Skin (Py4) and pancreas (MS1). Adjacent lane (H2O) shows template negative control. <italic>Gapdh</italic> was loading control (lower band), (<italic>n = 5</italic>). <bold>(c)</bold> ELISA quantification of sVegfr-2 protein in supernatant of blood and lymphatic endothelial cells (<italic>n</italic> = 3). <bold>(d)</bold> Immunofluorescence of sVegfr-2 (red) in the pulmonary microvasculature (Cd31<sup>+</sup> vessel – green). Cell nuclei stained with DAPI. Scale bar, 50 μm. (<bold>e</bold>) ELISA quantification of sVegfr-2 levels in plasma (<italic>n</italic> = 16). *, <italic>P</italic> < 0.05; Significance by Mann Whitney U test. (<bold>c,e</bold>) Error bars depict s.e.m.</p></caption><graphic xlink:href="nihms-131529-f0005"></graphic></fig><fig id="F6" position="float"><label>Figure 6</label><caption><p>sVEGFR-2 exists in humans and inhibits human lymphangioma cell proliferation. <bold>(a)</bold> PCR cloning of open-reading-frame of <italic>VEGFR2</italic> from human umbilical vein endothelial cells. <bold>(b)</bold> sVEGFR-2 immunolocalization (brown) in the human cornea using AA21129. Cell nuclei stained blue by hematoxylin. <bold>(c,d)</bold> Proliferation of lymphatic endothelial cells isolated from two children with lymphangioma, stimulated by VEGF-C and treated with sVEGFR-2 or bovine serum albumin (BSA), quantified by BrdU uptake. (<italic>n</italic> = 6–9); <bold>c</bold>, Patient #1 is a 4-month old child; <bold>d</bold>, Patient #2 is a 10-month-old child. NS, not significant; *, <italic>P</italic> < 0.05; Significance by Mann Whitney U test. Error bars depict s.e.m.</p></caption><graphic xlink:href="nihms-131529-f0006"></graphic></fig></floats-group></pmc><affiliations><list><country><li>Allemagne</li><li>Japon</li><li>États-Unis</li></country></list><tree><country name="États-Unis"><noRegion><name sortKey="Albuquerque, Romulo J C" sort="Albuquerque, Romulo J C" uniqKey="Albuquerque R" first="Romulo J. C." last="Albuquerque">Romulo J. C. Albuquerque</name></noRegion><name sortKey="Albuquerque, Romulo J C" sort="Albuquerque, Romulo J C" uniqKey="Albuquerque R" first="Romulo J. C." last="Albuquerque">Romulo J. C. Albuquerque</name><name sortKey="Alexander, Jonathan S" sort="Alexander, Jonathan S" uniqKey="Alexander J" first="Jonathan S." last="Alexander">Jonathan S. Alexander</name><name sortKey="Ambati, Balamurali K" sort="Ambati, Balamurali K" uniqKey="Ambati B" first="Balamurali K." last="Ambati">Balamurali K. Ambati</name><name sortKey="Ambati, Balamurali K" sort="Ambati, Balamurali K" uniqKey="Ambati B" first="Balamurali K." last="Ambati">Balamurali K. Ambati</name><name sortKey="Ambati, Jayakrishna" sort="Ambati, Jayakrishna" uniqKey="Ambati J" first="Jayakrishna" last="Ambati">Jayakrishna Ambati</name><name sortKey="Ambati, Jayakrishna" sort="Ambati, Jayakrishna" uniqKey="Ambati J" first="Jayakrishna" last="Ambati">Jayakrishna Ambati</name><name sortKey="Baffi, Judit Z" sort="Baffi, Judit Z" uniqKey="Baffi J" first="Judit Z." last="Baffi">Judit Z. Baffi</name><name sortKey="Brekken, Rolf A" sort="Brekken, Rolf A" uniqKey="Brekken R" first="Rolf A." last="Brekken">Rolf A. Brekken</name><name sortKey="Capoor, Seema" sort="Capoor, Seema" uniqKey="Capoor S" first="Seema" last="Capoor">Seema Capoor</name><name sortKey="Chappell, Joe" sort="Chappell, Joe" uniqKey="Chappell J" first="Joe" last="Chappell">Joe Chappell</name><name sortKey="Cho, Won Gil" sort="Cho, Won Gil" uniqKey="Cho W" first="Won Gil" last="Cho">Won Gil Cho</name><name sortKey="Dridi, Sami" sort="Dridi, Sami" uniqKey="Dridi S" first="Sami" last="Dridi">Sami Dridi</name><name sortKey="Green, Martha G" sort="Green, Martha G" uniqKey="Green M" first="Martha G." last="Green">Martha G. Green</name><name sortKey="Kaneko, Hiroki" sort="Kaneko, Hiroki" uniqKey="Kaneko H" first="Hiroki" last="Kaneko">Hiroki Kaneko</name><name sortKey="Kleinman, Mark E" sort="Kleinman, Mark E" uniqKey="Kleinman M" first="Mark E." last="Kleinman">Mark E. Kleinman</name><name sortKey="Peterson, Martha L" sort="Peterson, Martha L" uniqKey="Peterson M" first="Martha L." last="Peterson">Martha L. Peterson</name><name sortKey="Takeda, Atsunobu" sort="Takeda, Atsunobu" uniqKey="Takeda A" first="Atsunobu" last="Takeda">Atsunobu Takeda</name><name sortKey="Yamada, Kiyoshi" sort="Yamada, Kiyoshi" uniqKey="Yamada K" first="Kiyoshi" last="Yamada">Kiyoshi Yamada</name></country><country name="Japon"><noRegion><name sortKey="Hayashi, Takahiko" sort="Hayashi, Takahiko" uniqKey="Hayashi T" first="Takahiko" last="Hayashi">Takahiko Hayashi</name></noRegion><name sortKey="Amano, Shiro" sort="Amano, Shiro" uniqKey="Amano S" first="Shiro" last="Amano">Shiro Amano</name><name sortKey="Hirashima, Masanori" sort="Hirashima, Masanori" uniqKey="Hirashima M" first="Masanori" last="Hirashima">Masanori Hirashima</name><name sortKey="Mizuki, Nobuhisa" sort="Mizuki, Nobuhisa" uniqKey="Mizuki N" first="Nobuhisa" last="Mizuki">Nobuhisa Mizuki</name><name sortKey="Usui, Tomohiko" sort="Usui, Tomohiko" uniqKey="Usui T" first="Tomohiko" last="Usui">Tomohiko Usui</name><name sortKey="Yamagami, Satoru" sort="Yamagami, Satoru" uniqKey="Yamagami S" first="Satoru" last="Yamagami">Satoru Yamagami</name></country><country name="Allemagne"><noRegion><name sortKey="Wilting, Jorg" sort="Wilting, Jorg" uniqKey="Wilting J" first="Jörg" last="Wilting">Jörg Wilting</name></noRegion><name sortKey="Weich, Herbert A" sort="Weich, Herbert A" uniqKey="Weich H" first="Herbert A." last="Weich">Herbert A. 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