TY - JOUR
T1 - Tyrosine-protein kinase Yes controls endothelial junctional plasticity and barrier integrity by regulating VE-cadherin phosphorylation and endocytosis
AU - Jin, Yi
AU - Ding, Yindi
AU - Richards, Mark
AU - Kaakinen, Mika
AU - Giese, Wolfgang
AU - Baumann, Elisabeth
AU - Szymborska, Anna
AU - Rosa, André
AU - Nordling, Sofia
AU - Schimmel, Lilian
AU - Akmeriç, Emir Bora
AU - Pena, Andreia
AU - Nwadozi, Emmanuel
AU - Jamalpour, Maria
AU - Holstein, Katrin
AU - Sáinz-Jaspeado, Miguel
AU - Bernabeu, Miguel O.
AU - Welsh, Michael
AU - Gordon, Emma
AU - Franco, Claudio A.
AU - Vestweber, Dietmar
AU - Eklund, Lauri
AU - Gerhardt, Holger
AU - Claesson-Welsh, Lena
N1 - Funding Information:
We gratefully acknowledge E. Dejana (Uppsala University; IFOM Milano) and F. Osenigo (IFOM, Milano) for the pY658-VE-cadherin antibody. Euro-BioImaging ERIC and Biocenter Oulu Electron Microscopy core facility supported by University of Oulu and Biocenter Finland are acknowledged for providing infrastructure allowing ultrastructural analyses. We gratefully acknowledge A. Dubrac, Université de Montréal for providing annotations for the single-cell RNA-sequencing data of retinas, R. Benedito, Centro Nacional de Investigaciones Cardiovasculares for providing the iSuRe-Cre mouse model and R. Adams, Max-Planck Institute for providing Cdh5(PAC)-CreER mice. This study was supported by the Swedish Research Council (2020-01349), the Knut and Alice Wallenberg foundation (KAW 2020.0057 and KAW 2019.0276), Fondation Leducq Transatlantic Network of Excellence Grant in Neurovascular Disease (17 CVD 03) to L.C.W., H.G., C.A.F. and M.B., Fundação para a Ciência e Tecnologia (PTDC/MED-PAT/31639/2017; CEECIND/04251/2017), European Research Council (679368) to C.A.F., Deutsche Forschungsgemeinschaft (KFO342, P2; CRC1450, B03) to D.V., the Academy of Finland (LE380986) and the Sigrid Jusélius Foundation to L.E. The processing of single-cell RNA-sequencing data was enabled by resources in project SNIC 2021/22-221 provided by the Swedish National Infrastructure for Computing at UPPMAX, partially funded by the Swedish Research Council through grant agreement no. 2018-05973. T2
Funding Information:
We gratefully acknowledge E. Dejana (Uppsala University; IFOM Milano) and F. Osenigo (IFOM, Milano) for the pY658-VE-cadherin antibody. Euro-BioImaging ERIC and Biocenter Oulu Electron Microscopy core facility supported by University of Oulu and Biocenter Finland are acknowledged for providing infrastructure allowing ultrastructural analyses. We gratefully acknowledge A. Dubrac, Université de Montréal for providing annotations for the single-cell RNA-sequencing data of retinas, R. Benedito, Centro Nacional de Investigaciones Cardiovasculares for providing the iSuRe-Cre mouse model and R. Adams, Max-Planck Institute for providing Cdh5(PAC)-CreERT2mice. This study was supported by the Swedish Research Council (2020-01349), the Knut and Alice Wallenberg foundation (KAW 2020.0057 and KAW 2019.0276), Fondation Leducq Transatlantic Network of Excellence Grant in Neurovascular Disease (17 CVD 03) to L.C.W., H.G., C.A.F. and M.B., Fundação para a Ciência e Tecnologia (PTDC/MED-PAT/31639/2017; CEECIND/04251/2017), European Research Council (679368) to C.A.F., Deutsche Forschungsgemeinschaft (KFO342, P2; CRC1450, B03) to D.V., the Academy of Finland (LE380986) and the Sigrid Jusélius Foundation to L.E. The processing of single-cell RNA-sequencing data was enabled by resources in project SNIC 2021/22-221 provided by the Swedish National Infrastructure for Computing at UPPMAX, partially funded by the Swedish Research Council through grant agreement no. 2018-05973.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - Vascular endothelial (VE)-cadherin in endothelial adherens junctions is an essential component of the vascular barrier, critical for tissue homeostasis and implicated in diseases such as cancer and retinopathies. Inhibitors of Src cytoplasmic tyrosine kinase have been applied to suppress VE-cadherin tyrosine phosphorylation and prevent excessive leakage, edema and high interstitial pressure. Here we show that the Src-related Yes tyrosine kinase, rather than Src, is localized at endothelial cell (EC) junctions where it becomes activated in a flow-dependent manner. EC-specific Yes1 deletion suppresses VE-cadherin phosphorylation and arrests VE-cadherin at EC junctions. This is accompanied by loss of EC collective migration and exaggerated agonist-induced macromolecular leakage. Overexpression of Yes1 causes ectopic VE-cadherin phosphorylation, while vascular leakage is unaffected. In contrast, in EC-specific Src deficiency, VE-cadherin internalization is maintained and leakage is suppressed. In conclusion, Yes-mediated phosphorylation regulates constitutive VE-cadherin turnover, thereby maintaining endothelial junction plasticity and vascular integrity.
AB - Vascular endothelial (VE)-cadherin in endothelial adherens junctions is an essential component of the vascular barrier, critical for tissue homeostasis and implicated in diseases such as cancer and retinopathies. Inhibitors of Src cytoplasmic tyrosine kinase have been applied to suppress VE-cadherin tyrosine phosphorylation and prevent excessive leakage, edema and high interstitial pressure. Here we show that the Src-related Yes tyrosine kinase, rather than Src, is localized at endothelial cell (EC) junctions where it becomes activated in a flow-dependent manner. EC-specific Yes1 deletion suppresses VE-cadherin phosphorylation and arrests VE-cadherin at EC junctions. This is accompanied by loss of EC collective migration and exaggerated agonist-induced macromolecular leakage. Overexpression of Yes1 causes ectopic VE-cadherin phosphorylation, while vascular leakage is unaffected. In contrast, in EC-specific Src deficiency, VE-cadherin internalization is maintained and leakage is suppressed. In conclusion, Yes-mediated phosphorylation regulates constitutive VE-cadherin turnover, thereby maintaining endothelial junction plasticity and vascular integrity.
UR - http://www.scopus.com/inward/record.url?scp=85161153971&partnerID=8YFLogxK
U2 - 10.1038/s44161-022-00172-z
DO - 10.1038/s44161-022-00172-z
M3 - Article
C2 - 37936984
AN - SCOPUS:85161153971
SN - 2731-0590
VL - 1
SP - 1156
EP - 1173
JO - Nature Cardiovascular Research
JF - Nature Cardiovascular Research
IS - 12
ER -
