Premium
Identification of ILK as a critical regulator of VEGFR 3 signalling and lymphatic vascular growth
Author(s) -
Urner Sofia,
PlanasPaz Lara,
Hilger Laura Sophie,
Henning Carina,
Branopolski Anna,
KellyGoss Molly,
Stanczuk Lukas,
Pitter Bettina,
Montanez Eloi,
Peirce Shayn M,
Mäkinen Taija,
Lammert Eckhard
Publication year - 2018
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201899322
Subject(s) - biology , regulator , microbiology and biotechnology , lymphatic endothelium , signalling , vegf receptors , lymphatic system , immunology , genetics , cancer research , gene
Vascular endothelial growth factor receptor‐3 ( VEGFR 3) signalling promotes lymphangiogenesis. While there are many reported mechanisms of VEGFR 3 activation, there is little understanding of how VEGFR 3 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 VEGFR 3 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 LEC s triggers VEGFR 3 tyrosine phosphorylation and proliferation. ILK is further found to impede interactions between VEGFR 3 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 VEGFR 3. Our data suggest that ILK facilitates mechanically regulated VEGFR 3 signalling via controlling its interaction with β1 integrin and thus ensures proper development of lymphatic vessels.