Role of Endothelial YAP1/TAZ Signaling in Lung Regeneration

Abstract

Angiogenesis, the formation of new blood capillaries, plays a key role in organ development, homeostasis and regeneration. We have reported that angiogenesis is stimulated during regenerative lung growth after unilateral pneumonectomy (PNX). In addition to chemical factors, mechanical forces play important roles in endothelial cell (EC) growth and differentiation. It is known that mechanical forces change during regenerative lung growth after PNX. However, the mechanism by which changes in mechanical forces after PNX control angiogenesis during regenerative lung growth remains unclear. The mechanosensitive transcriptional co‐activators, Yes‐associated protein (YAP1) and transcriptional co‐activator with PDZ‐binding motif (TAZ), control angiogenesis. Knockdown of endothelial YAP1 suppresses compensatory lung growth after unilateral PNX in adult mice. Parenchymal deformation due to expansion of the remaining lobes and increases in alveolar microvascular perfusion of the remaining lobes after PNX play key roles in the post‐PNX lung growth. Insertion of silicone prosthesis to replace an excised lobe prevents post‐PNX lung growth and decreases YAP1/TAZ expression. Ligation of one lobar pulmonary artery after PNX stimulates compensatory growth of the remaining non‐occluded lung lobes. To analyze the effects of endothelial YAP1 on angiogenesis and epithelial morphogenesis during regenerative lung growth, we implanted fibrin gel on the mouse lung after PNX and found that knockdown of endothelial YAP1 inhibits angiogenesis and alveolar epithelial cell recruitment into hydrogel implanted on the mouse lung. These results suggest that changes in mechanical forces after PNX contributes to regenerative lung growth through endothelial YAP1/TAZ signaling and modulation of endothelial YAP1/TAZ could be novel interventions for the improvement of the strategies for lung regeneration.Support or Funding InformationNIHR21AG054830, MCW Research Affair Committee New Investigator AwardThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.