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.
LPHN2 inhibits vascular permeability by differential control of endothelial cell adhesion
C. Camillo’s present address is Department of Surgery, Columbia University, New York, NY.
- Award Id(s): 13016,16702,21315,19923,20366,20119
- Award Id(s): GGP09175
- Award Id(s): CUP D84I19002940005
- Award Id(s): 647057 - rEnDOx
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Chiara 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 Tamagnone, Donatella Valdembri, Massimo M. Santoro, Guido Serini; LPHN2 inhibits vascular permeability by differential control of endothelial cell adhesion. J Cell Biol 1 November 2021; 220 (11): e202006033. doi: https://doi.org/10.1083/jcb.202006033
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