Identification of ILK as a critical regulator of VEGFR3 signalling and lymphatic vascular growth
| Autor: | Eckhard Lammert, Anna Branopolski, Laura Sophie Hilger, Sofia Urner, Taija Makinen, Molly R. Kelly-Goss, Lara Planas-Paz, Eloi Montanez, Lukas Stanczuk, Shayn M. Peirce, Bettina Pitter, Carina Henning |
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| Rok vydání: | 2019 |
| Předmět: |
Integrins
Vascular Biology & Angiogenesis lymphatic vasculature integrin‐linked kinase Integrines chemistry.chemical_compound Mice 0302 clinical medicine Protein kinases Lymphangiogenesis Phosphorylation Cells Cultured 0303 health sciences biology Factor de creixement de l'endoteli vascular General Neuroscience Integrin beta1 Articles Metabolisme Cell biology Vascular endothelial growth factor Endothelial stem cell Lymphatic system embryonic structures Female VEGFR3 Signal Transduction Integrin Protein Serine-Threonine Kinases General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Vascular endothelial growth factors β1 integrin Genetics Animals Humans Integrin-linked kinase Lymph sacs mechanical stimulation Molecular Biology 030304 developmental biology Cell Proliferation Lymphatic Vessels General Immunology and Microbiology Tyrosine phosphorylation Vascular Endothelial Growth Factor Receptor-3 Proteïnes quinases Disease Models Animal Metabolism chemistry biology.protein Development & Differentiation 030217 neurology & neurosurgery Genètica |
| Zdroj: | Dipòsit Digital de la UB Universidad de Barcelona The EMBO Journal |
| Popis: | Vascular endothelial growth factor receptor‐3 (VEGFR3) signalling promotes lymphangiogenesis. While there are many reported mechanisms of VEGFR3 activation, there is little understanding of how VEGFR3 signalling is attenuated to prevent lymphatic vascular overgrowth and ensure proper lymph vessel development. Here, we show that endothelial cell‐specific depletion of integrin‐linked kinase (ILK) in mouse embryos hyper‐activates VEGFR3 signalling and leads to overgrowth of the jugular lymph sacs/primordial thoracic ducts, oedema and embryonic lethality. Lymphatic endothelial cell (LEC)‐specific deletion of Ilk in adult mice initiates lymphatic vascular expansion in different organs, including cornea, skin and myocardium. Knockdown of ILK in human LECs triggers VEGFR3 tyrosine phosphorylation and proliferation. ILK is further found to impede interactions between VEGFR3 and β1 integrin in vitro and in vivo, and endothelial cell‐specific deletion of an Itgb1 allele rescues the excessive lymphatic vascular growth observed upon ILK depletion. Finally, mechanical stimulation disrupts the assembly of ILK and β1 integrin, releasing the integrin to enable its interaction with VEGFR3. Our data suggest that ILK facilitates mechanically regulated VEGFR3 signalling via controlling its interaction with β1 integrin and thus ensures proper development of lymphatic vessels. |
| Databáze: | OpenAIRE |
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