The Schlemm’s canal is a VEGF-C/VEGFR-3–responsive lymphatic-like vessel
Identifieur interne : 002437 ( Main/Exploration ); précédent : 002436; suivant : 002438The Schlemm’s canal is a VEGF-C/VEGFR-3–responsive lymphatic-like vessel
Auteurs : Aleksanteri Aspelund [Finlande] ; Tuomas Tammela [Finlande] ; Salli Antila [Finlande] ; Harri Nurmi [Finlande] ; Veli-Matti Lepp Nen [Finlande] ; Georgia Zarkada [Finlande] ; Lukas Stanczuk [Suède] ; Mathias Francois [Australie] ; Taija M Kinen [Suède] ; Pipsa Saharinen [Finlande] ; Ilkka Immonen [Finlande] ; Kari Alitalo [Finlande]Source :
- The Journal of Clinical Investigation [ 0021-9738 ] ; 2014.
Abstract
In glaucoma, aqueous outflow into the Schlemm’s canal (SC) is obstructed. Despite striking structural and functional similarities with the lymphatic vascular system, it is unknown whether the SC is a blood or lymphatic vessel. Here, we demonstrated the expression of lymphatic endothelial cell markers by the SC in murine and zebrafish models as well as in human eye tissue. The initial stages of SC development involved induction of the transcription factor PROX1 and the lymphangiogenic receptor tyrosine kinase VEGFR-3 in venous endothelial cells in postnatal mice. Using gene deletion and function-blocking antibodies in mice, we determined that the lymphangiogenic growth factor VEGF-C and its receptor, VEGFR-3, are essential for SC development. Delivery of VEGF-C into the adult eye resulted in sprouting, proliferation, and growth of SC endothelial cells, whereas VEGF-A obliterated the aqueous outflow system. Furthermore, a single injection of recombinant VEGF-C induced SC growth and was associated with trend toward a sustained decrease in intraocular pressure in adult mice. These results reveal the evolutionary conservation of the lymphatic-like phenotype of the SC, implicate VEGF-C and VEGFR-3 as critical regulators of SC lymphangiogenesis, and provide a basis for further studies on therapeutic manipulation of the SC with VEGF-C in glaucoma treatment.
Url:
DOI: 10.1172/JCI75395
PubMed: 25061878
PubMed Central: 4153703
Affiliations:
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lymphatic-like vessel</title><author><name sortKey="Aspelund, Aleksanteri" sort="Aspelund, Aleksanteri" uniqKey="Aspelund A" first="Aleksanteri" last="Aspelund">Aleksanteri Aspelund</name><affiliation wicri:level="4"><nlm:aff id="JCI75395">Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Finlande</country><wicri:regionArea>Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki</wicri:regionArea><orgName type="university">Université d'Helsinki</orgName><placeName><settlement type="city">Helsinki</settlement><region type="région" nuts="2">Uusimaa</region></placeName></affiliation></author><author><name sortKey="Tammela, Tuomas" sort="Tammela, Tuomas" uniqKey="Tammela T" first="Tuomas" last="Tammela">Tuomas Tammela</name><affiliation wicri:level="4"><nlm:aff id="JCI75395">Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Finlande</country><wicri:regionArea>Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki</wicri:regionArea><orgName type="university">Université d'Helsinki</orgName><placeName><settlement type="city">Helsinki</settlement><region type="région" nuts="2">Uusimaa</region></placeName></affiliation></author><author><name sortKey="Antila, Salli" sort="Antila, Salli" uniqKey="Antila S" first="Salli" last="Antila">Salli Antila</name><affiliation wicri:level="4"><nlm:aff id="JCI75395">Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Finlande</country><wicri:regionArea>Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki</wicri:regionArea><orgName type="university">Université d'Helsinki</orgName><placeName><settlement type="city">Helsinki</settlement><region type="région" nuts="2">Uusimaa</region></placeName></affiliation></author><author><name sortKey="Nurmi, Harri" sort="Nurmi, Harri" uniqKey="Nurmi H" first="Harri" last="Nurmi">Harri Nurmi</name><affiliation wicri:level="4"><nlm:aff id="JCI75395">Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Finlande</country><wicri:regionArea>Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki</wicri:regionArea><orgName type="university">Université d'Helsinki</orgName><placeName><settlement type="city">Helsinki</settlement><region type="région" nuts="2">Uusimaa</region></placeName></affiliation></author><author><name sortKey="Lepp Nen, Veli Matti" sort="Lepp Nen, Veli Matti" uniqKey="Lepp Nen V" first="Veli-Matti" last="Lepp Nen">Veli-Matti Lepp Nen</name><affiliation wicri:level="4"><nlm:aff id="JCI75395">Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Finlande</country><wicri:regionArea>Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki</wicri:regionArea><orgName type="university">Université d'Helsinki</orgName><placeName><settlement type="city">Helsinki</settlement><region type="région" nuts="2">Uusimaa</region></placeName></affiliation></author><author><name sortKey="Zarkada, Georgia" sort="Zarkada, Georgia" uniqKey="Zarkada G" first="Georgia" last="Zarkada">Georgia Zarkada</name><affiliation wicri:level="4"><nlm:aff id="JCI75395">Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Finlande</country><wicri:regionArea>Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki</wicri:regionArea><orgName type="university">Université d'Helsinki</orgName><placeName><settlement type="city">Helsinki</settlement><region type="région" nuts="2">Uusimaa</region></placeName></affiliation></author><author><name sortKey="Stanczuk, Lukas" sort="Stanczuk, Lukas" uniqKey="Stanczuk L" first="Lukas" last="Stanczuk">Lukas Stanczuk</name><affiliation wicri:level="1"><nlm:aff id="JCI75395">Department of Immunology, Genetics and Pathology, University of Uppsala, Uppsala, Sweden.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Suède</country><wicri:regionArea>Department of Immunology, Genetics and Pathology, University of Uppsala, Uppsala</wicri:regionArea><wicri:noRegion>Uppsala</wicri:noRegion></affiliation></author><author><name sortKey="Francois, Mathias" sort="Francois, Mathias" uniqKey="Francois M" first="Mathias" last="Francois">Mathias Francois</name><affiliation wicri:level="1"><nlm:aff id="JCI75395">Genomics of Development and Disease Division, University of Queensland, Brisbane, Australia.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Australie</country><wicri:regionArea>Genomics of Development and Disease Division, University of Queensland, Brisbane</wicri:regionArea><wicri:noRegion>Brisbane</wicri:noRegion></affiliation></author><author><name sortKey="M Kinen, Taija" sort="M Kinen, Taija" uniqKey="M Kinen T" first="Taija" last="M Kinen">Taija M Kinen</name><affiliation wicri:level="1"><nlm:aff id="JCI75395">Department of Immunology, Genetics and Pathology, University of Uppsala, Uppsala, Sweden.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Suède</country><wicri:regionArea>Department of Immunology, Genetics and Pathology, University of Uppsala, Uppsala</wicri:regionArea><wicri:noRegion>Uppsala</wicri:noRegion></affiliation></author><author><name sortKey="Saharinen, Pipsa" sort="Saharinen, Pipsa" uniqKey="Saharinen P" first="Pipsa" last="Saharinen">Pipsa Saharinen</name><affiliation wicri:level="4"><nlm:aff id="JCI75395">Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Finlande</country><wicri:regionArea>Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki</wicri:regionArea><orgName type="university">Université d'Helsinki</orgName><placeName><settlement type="city">Helsinki</settlement><region type="région" nuts="2">Uusimaa</region></placeName></affiliation></author><author><name sortKey="Immonen, Ilkka" sort="Immonen, Ilkka" uniqKey="Immonen I" first="Ilkka" last="Immonen">Ilkka Immonen</name><affiliation wicri:level="1"><nlm:aff id="JCI75395">Department of Ophthalmology, Helsinki University Central Hospital, Helsinki, Finland.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Finlande</country><wicri:regionArea>Department of Ophthalmology, Helsinki University Central Hospital, Helsinki</wicri:regionArea><wicri:noRegion>Helsinki</wicri:noRegion></affiliation></author><author><name sortKey="Alitalo, Kari" sort="Alitalo, Kari" uniqKey="Alitalo K" first="Kari" last="Alitalo">Kari Alitalo</name><affiliation wicri:level="4"><nlm:aff id="JCI75395">Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Finlande</country><wicri:regionArea>Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki</wicri:regionArea><orgName type="university">Université d'Helsinki</orgName><placeName><settlement type="city">Helsinki</settlement><region type="région" nuts="2">Uusimaa</region></placeName><placeName><settlement type="city">Helsinki</settlement><region type="région" nuts="2">Uusimaa</region></placeName><orgName type="university">Université d'Helsinki</orgName></affiliation></author></analytic><series><title level="j">The Journal of Clinical Investigation</title><idno type="ISSN">0021-9738</idno><idno type="eISSN">1558-8238</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>In glaucoma, aqueous outflow into the Schlemm’s canal (SC) is obstructed. Despite
striking structural and functional similarities with the lymphatic vascular system, it is
unknown whether the SC is a blood or lymphatic vessel. Here, we demonstrated the
expression of lymphatic endothelial cell markers by the SC in murine and zebrafish models
as well as in human eye tissue. The initial stages of SC development involved induction of
the transcription factor PROX1 and the lymphangiogenic receptor tyrosine kinase VEGFR-3 in
venous endothelial cells in postnatal mice. Using gene deletion and function-blocking
antibodies in mice, we determined that the lymphangiogenic growth factor VEGF-C and its
receptor, VEGFR-3, are essential for SC development. Delivery of VEGF-C into the adult eye
resulted in sprouting, proliferation, and growth of SC endothelial cells, whereas VEGF-A
obliterated the aqueous outflow system. Furthermore, a single injection of recombinant
VEGF-C induced SC growth and was associated with trend toward a sustained decrease in
intraocular pressure in adult mice. These results reveal the evolutionary conservation of
the lymphatic-like phenotype of the SC, implicate VEGF-C and VEGFR-3 as critical
regulators of SC lymphangiogenesis, and provide a basis for further studies on therapeutic
manipulation of the SC with VEGF-C in glaucoma treatment.</p></div></front></TEI><affiliations><list><country><li>Australie</li><li>Finlande</li><li>Suède</li></country><region><li>Uusimaa</li></region><settlement><li>Helsinki</li></settlement><orgName><li>Université d'Helsinki</li></orgName></list><tree><country name="Finlande"><region name="Uusimaa"><name sortKey="Aspelund, Aleksanteri" sort="Aspelund, Aleksanteri" uniqKey="Aspelund A" first="Aleksanteri" last="Aspelund">Aleksanteri Aspelund</name></region><name sortKey="Alitalo, Kari" sort="Alitalo, Kari" uniqKey="Alitalo K" first="Kari" last="Alitalo">Kari Alitalo</name><name sortKey="Antila, Salli" sort="Antila, Salli" uniqKey="Antila S" first="Salli" last="Antila">Salli Antila</name><name sortKey="Immonen, Ilkka" sort="Immonen, Ilkka" uniqKey="Immonen I" first="Ilkka" last="Immonen">Ilkka Immonen</name><name sortKey="Lepp Nen, Veli Matti" sort="Lepp Nen, Veli Matti" uniqKey="Lepp Nen V" first="Veli-Matti" last="Lepp Nen">Veli-Matti Lepp Nen</name><name sortKey="Nurmi, Harri" sort="Nurmi, Harri" uniqKey="Nurmi H" first="Harri" last="Nurmi">Harri Nurmi</name><name sortKey="Saharinen, Pipsa" sort="Saharinen, Pipsa" uniqKey="Saharinen P" first="Pipsa" last="Saharinen">Pipsa Saharinen</name><name sortKey="Tammela, Tuomas" sort="Tammela, Tuomas" uniqKey="Tammela T" first="Tuomas" last="Tammela">Tuomas Tammela</name><name sortKey="Zarkada, Georgia" sort="Zarkada, Georgia" uniqKey="Zarkada G" first="Georgia" last="Zarkada">Georgia Zarkada</name></country><country name="Suède"><noRegion><name sortKey="Stanczuk, Lukas" sort="Stanczuk, Lukas" uniqKey="Stanczuk L" first="Lukas" last="Stanczuk">Lukas Stanczuk</name></noRegion><name sortKey="M Kinen, Taija" sort="M Kinen, Taija" uniqKey="M Kinen T" first="Taija" last="M Kinen">Taija M Kinen</name></country><country name="Australie"><noRegion><name sortKey="Francois, Mathias" sort="Francois, Mathias" uniqKey="Francois M" first="Mathias" last="Francois">Mathias Francois</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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