Role of endothelial Lats1 and Lats2 in endothelial response to flow

We report a critical requirement for Lats1/2 in adapting to blood flow during vascular development. When Lats1/2 are genetically deleted in ECs, embryos develop severe defects in blood vessel formation, which lead to embryonic lethality by E11.5. Vessel patterning and circulation initiate properly; however remodeling of the initial vascular plexus fails due to lumen collapse.

Lats1/2 depletion in cultured ECs leads to failed polarization, elongation, and VE-cadherin (VEcad) junctional maturation under flow. Finally, YAP/TAZ co-depletion in Lats1/2 depleted conditions leads to a partial rescue of phenotypes in vivo and in vitro. Our results suggest that Lats1/2 deficient cells no longer respond to laminar shear stress, in vivo and in vitro.

This work identifies Lats1 and Lats2 as critical transducers of biomechanical cues during early blood vessel remodeling. This study provides new targets for treating vascular diseases and new directions for efforts to generate vascularized tissues for replacement therapies.