LATS1/2 inactivation drives a distinct venous endothelial cell response that contributes to fibrotic remodeling of the lung
TL;DR
These findings identify LATS1/2-mediated restraint of YAP/TAZ as essential for lung endothelial homeostasis and highlight a distinct venous cell response as a direct contributor to fibrotic lung remodeling.
Abstract
Endothelial dysfunction is recognized to contribute to chronic tissue remodeling in the lung, yet endothelial-derived mechanisms driving these processes remain largely undefined. Here, we show that endothelial inactivation of the LATS1 and LATS2 kinases, key suppressors of the transcriptional regulators YAP and TAZ, elicits distinct responses depending on endothelial identity within different pulmonary vascular beds. Our data indicate that LATS1/2 inactivation in general capillary endothelial cells induces a reactive capillary injury-like state, whereas a separate endothelial population located within veins adopts a distinct profibrotic state. We show that expansion of this reactive venous endothelial cell population, which is marked by EBF1 and ACKR1 expression, is associated with fibroblast activation, macrophage accumulation, and epithelial remodeling, collectively generating a microenvironment characteristic of fibrotic lung disease. We further demonstrate that pharmacologic inhibition of YAP/TAZ-TEAD signaling prevents stromal and immune remodeling and fibrotic lesion formation following endothelial LATS1/2 inactivation. These findings identify LATS1/2-mediated restraint of YAP/TAZ as essential for lung endothelial homeostasis and highlight a distinct venous cell response as a direct contributor to fibrotic lung remodeling.