Tadanori Mammoto, Priscilla Kyi, Mikaela Scheer, Tendai Hunyenyiwa, Elaheh Hashemi, Xiaolong Ma, Christopher Turner, Chien-Wei Lin, Subramaniam Malarkannan, Akiko Mammoto
Mechanical forces altered after unilateral pneumonectomy (PNX) control post-PNX lung growth. Here, we demonstrate that post-PNX endothelial regeneration is stimulated at the peripheral region of the mouse lung, requiring the focal adhesion (FA) protein, paxillin, while inhibition of mechanical tension attenuates the effects. Paxillin mediates stretching-induced YAP1-TEAD1 signaling, which stimulates GATA2 activity on angiogenic factor angiopoietin-2 (ANGPT2) transcription in endothelial cells (ECs), dictating post-PNX endothelial regeneration at the peripheral region. Deleting endothelial paxillin suppresses expression of GATA2 in the specific EC subtype, capillary type 1 ECs (CAP1s) following PNX. Extracellular matrix protein, collagen VI that impacts cell mechanical responses is expressed more at the peripheral region in the post-PNX mouse lungs, which drives paxillin expression, leading to EC regeneration. Mechanosensitive paxillin signaling in ECs mediates spatial control of post-PNX endothelial regeneration.