RT Journal Article
SR Electronic
T1 LPHN2 inhibits vascular permeability by differential control of endothelial cell adhesion
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.04.28.065979
DO 10.1101/2020.04.28.065979
A1 Chiara Camillo
A1 Nicola Facchinello
A1 Giulia Villari
A1 Giulia Mana
A1 Noemi Gioelli
A1 Chiara Sandri
A1 Matteo Astone
A1 Dora Tortarolo
A1 Fabiana Clapero
A1 Dafne Gays
A1 Roxana E. Oberkersch
A1 Marco Arese
A1 Luca Tamagnone
A1 Donatella Valdembri
A1 Massimo Santoro
A1 Guido Serini
YR 2021
UL http://biorxiv.org/content/early/2021/08/31/2020.04.28.065979.abstract
AB Dynamic modulation of endothelial cell-to-cell and cell-to-extracellular matrix (ECM) adhesion is essential for blood vessel patterning and functioning. Yet, the molecular mechanisms involved in this process have not been completely deciphered. We identify the adhesion G protein-coupled receptor (ADGR) Latrophilin 2 (LPHN2) as a novel determinant of endothelial cell (EC) adhesion and barrier function. In cultured ECs, endogenous LPHN2 localizes at ECM contacts, signals through cAMP/Rap1, and inhibits focal adhesion (FA) formation and nuclear localization of YAP/TAZ transcriptional regulators, while promoting tight junction (TJ) assembly. ECs also express an endogenous LPHN2 ligand, fibronectin-leucine-rich transmembrane 2 (FLRT2), that prevents ECM-elicited EC behaviors in a LPHN2-dependent manner. Vascular ECs of lphn2a knock-out zebrafish embryos become abnormally stretched, display a hyperactive YAP/TAZ pathway, and lack proper intercellular TJs. Consistently, blood vessels are hyperpermeable and intravascularly injected cancer cells extravasate more easily in lphn2a null animals. Thus, LPHN2 ligands, such as FLRT2, may be therapeutically exploited to interfere with cancer metastatic dissemination.SUMMARY Camillo et al. show that the LPHN2 receptor, upon activation by FLRT2 ligand, inhibits focal adhesion formation and promotes tight junction assembly in endothelial cells. Blood vessels of lphn2a null animals are hyperpermeable and injected cancer cells extravasate more easily.Competing Interest StatementThe authors have declared no competing interest.