Open AccessLPHN2 inhibits vascular permeability by differential control of endothelial cell adhesion
Author(s) -
Chiara Di Camillo,
Nicola Facchinello,
Giulia Villari,
Giulia Mana,
Noemi Gioelli,
Chiara Sandri,
Matteo Astone,
Dora Tortarolo,
Fabiana Clapero,
Dafne Gays,
Roxana E Oberkersch,
Marco Arese,
Luca Tamag,
Donatella Valdembri,
Massimo Santoro,
Guido Serini
Publication year - 2021
Publication title -
the journal of cell biology/the journal of cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.414
H-Index - 380
eISSN - 1540-8140
pISSN - 0021-9525
DOI - 10.1083/jcb.202006033
Subject(s) - microbiology and biotechnology , biology , fibronectin , extracellular matrix , cell adhesion , endothelial stem cell , vascular permeability , zebrafish , cell , biochemistry , in vitro , endocrinology , gene
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 an 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.