Modulation of VEGF-induced migration and network formation by lymphatic endothelial cells: Roles of platelets and podoplanin
Lymphatic endothelial cells (LEC) express the transmembrane receptor podoplanin whose only known endogenous ligand CLEC-2 is found on platelets. Both podoplanin and CLEC-2 are required for normal lymphangiogenesis as mice lacking either protein develop a blood-lymphatic mixing phenotype. We investig...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2018-07-01
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| Series: | Platelets |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/09537104.2017.1336210 |
| _version_ | 1797684306571689984 |
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| author | Stacey A. Langan Leyre Navarro-Núñez Steve P. Watson Gerard B. Nash |
| author_facet | Stacey A. Langan Leyre Navarro-Núñez Steve P. Watson Gerard B. Nash |
| author_sort | Stacey A. Langan |
| collection | DOAJ |
| description | Lymphatic endothelial cells (LEC) express the transmembrane receptor podoplanin whose only known endogenous ligand CLEC-2 is found on platelets. Both podoplanin and CLEC-2 are required for normal lymphangiogenesis as mice lacking either protein develop a blood-lymphatic mixing phenotype. We investigated the roles of podoplanin and its interaction with platelets in migration and tube formation by LEC. Addition of platelets or antibody-mediated crosslinking of podoplanin inhibited LEC migration induced by vascular endothelial growth factors (VEGF-A or VEGF-C), but did not modify basal migration or the response to basic fibroblast growth factor or epidermal growth factor. In addition, platelets and podoplanin crosslinking disrupted networks of LEC formed in co-culture with fibroblasts. Depletion of podoplanin in LEC using siRNA negated the pro-migratory effect of VEGF-A and VEGF-C. Inhibition of RhoA or Rho-kinase reduced LEC migration induced by VEGF-C, but had no further effect after crosslinking of podoplanin, suggesting that podoplanin is required for signaling downstream of VEGF-receptors but upstream of RhoA. Together, these data reveal for the first time that podoplanin is an intrinsic specific regulator of VEGF-mediated migration and network formation in LEC and identify crosslinking of podoplanin by platelets or antibodies as mechanisms to modulate this pathway. |
| first_indexed | 2024-03-12T00:27:45Z |
| format | Article |
| id | doaj.art-f71a51329dab4254a3058207774d5838 |
| institution | Directory Open Access Journal |
| issn | 0953-7104 1369-1635 |
| language | English |
| last_indexed | 2024-03-12T00:27:45Z |
| publishDate | 2018-07-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Platelets |
| spelling | doaj.art-f71a51329dab4254a3058207774d58382023-09-15T10:31:58ZengTaylor & Francis GroupPlatelets0953-71041369-16352018-07-0129548649510.1080/09537104.2017.13362101336210Modulation of VEGF-induced migration and network formation by lymphatic endothelial cells: Roles of platelets and podoplaninStacey A. Langan0Leyre Navarro-Núñez1Steve P. Watson2Gerard B. Nash3Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of BirminghamInstitute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of BirminghamInstitute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of BirminghamInstitute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of BirminghamLymphatic endothelial cells (LEC) express the transmembrane receptor podoplanin whose only known endogenous ligand CLEC-2 is found on platelets. Both podoplanin and CLEC-2 are required for normal lymphangiogenesis as mice lacking either protein develop a blood-lymphatic mixing phenotype. We investigated the roles of podoplanin and its interaction with platelets in migration and tube formation by LEC. Addition of platelets or antibody-mediated crosslinking of podoplanin inhibited LEC migration induced by vascular endothelial growth factors (VEGF-A or VEGF-C), but did not modify basal migration or the response to basic fibroblast growth factor or epidermal growth factor. In addition, platelets and podoplanin crosslinking disrupted networks of LEC formed in co-culture with fibroblasts. Depletion of podoplanin in LEC using siRNA negated the pro-migratory effect of VEGF-A and VEGF-C. Inhibition of RhoA or Rho-kinase reduced LEC migration induced by VEGF-C, but had no further effect after crosslinking of podoplanin, suggesting that podoplanin is required for signaling downstream of VEGF-receptors but upstream of RhoA. Together, these data reveal for the first time that podoplanin is an intrinsic specific regulator of VEGF-mediated migration and network formation in LEC and identify crosslinking of podoplanin by platelets or antibodies as mechanisms to modulate this pathway.http://dx.doi.org/10.1080/09537104.2017.1336210clec-2lymphangiogenesisplateletspodoplaninvegf |
| spellingShingle | Stacey A. Langan Leyre Navarro-Núñez Steve P. Watson Gerard B. Nash Modulation of VEGF-induced migration and network formation by lymphatic endothelial cells: Roles of platelets and podoplanin Platelets clec-2 lymphangiogenesis platelets podoplanin vegf |
| title | Modulation of VEGF-induced migration and network formation by lymphatic endothelial cells: Roles of platelets and podoplanin |
| title_full | Modulation of VEGF-induced migration and network formation by lymphatic endothelial cells: Roles of platelets and podoplanin |
| title_fullStr | Modulation of VEGF-induced migration and network formation by lymphatic endothelial cells: Roles of platelets and podoplanin |
| title_full_unstemmed | Modulation of VEGF-induced migration and network formation by lymphatic endothelial cells: Roles of platelets and podoplanin |
| title_short | Modulation of VEGF-induced migration and network formation by lymphatic endothelial cells: Roles of platelets and podoplanin |
| title_sort | modulation of vegf induced migration and network formation by lymphatic endothelial cells roles of platelets and podoplanin |
| topic | clec-2 lymphangiogenesis platelets podoplanin vegf |
| url | http://dx.doi.org/10.1080/09537104.2017.1336210 |
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