1 Department of Radiology and.
2 Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin.
Am J Respir Cell Mol Biol. 2019 Jan;60(1):117-127. doi: 10.1165/rcmb.2018-0105OC.
Angiogenesis, the formation of new blood capillaries, plays a key role in organ development and regeneration. Inhibition of lung angiogenesis through the blockade of angiogenic signaling pathways impairs compensatory and regenerative lung growth after unilateral pneumonectomy (PNX). The Hippo signaling transducer, Yes-associated protein (YAP) 1 binds to TEA domain transcription factor (TEAD) and controls organ size and regeneration. However, the role of endothelial YAP1 in lung vascular and alveolar morphogenesis remains unclear. In this report, we demonstrate that knockdown of YAP1 in endothelial cells (ECs) decreases angiogenic factor receptor Tie2 expression, and inhibits EC sprouting and epithelial cell budding in vitro and vascular and alveolar morphogenesis in the gel implanted on the mouse lung. The expression levels of YAP1, TEAD1, and Tie2 increase in ECs isolated from the remaining mouse lungs after unilateral PNX and vascular formation is stimulated in the post-PNX mouse lungs. Knockdown of endothelial YAP1 inhibits compensatory lung growth and vascular and alveolar morphogenesis after unilateral PNX. These findings suggest that endothelial YAP1 is required for lung vascular and alveolar regeneration and modulation of YAP1 in ECs may be novel interventions for the improvement of lung regeneration.
血管生成，即新毛细血管的形成，在器官发育和再生中起着关键作用。通过阻断血管生成信号通路抑制肺血管生成会损害单侧肺切除（PNX）后的代偿性和再生性肺生长。Hippo 信号转导蛋白 Yes 相关蛋白 1（YAP1）与 TEA 结构域转录因子（TEAD）结合，控制器官大小和再生。然而，内皮细胞 YAP1 在肺血管和肺泡形态发生中的作用仍不清楚。在本报告中，我们证明内皮细胞（ECs）中 YAP1 的敲低会降低血管生成因子受体 Tie2 的表达，并抑制体外 EC 出芽和上皮细胞出芽以及在植入小鼠肺的凝胶中的血管和肺泡形态发生。单侧 PNX 后，从剩余小鼠肺中分离出的 ECs 中 YAP1、TEAD1 和 Tie2 的表达水平增加，并且在 PNX 后小鼠肺中刺激血管形成。内皮细胞 YAP1 的敲低抑制了单侧 PNX 后的肺代偿性生长和血管及肺泡形态发生。这些发现表明内皮细胞 YAP1 是肺血管和肺泡再生所必需的，并且调节 ECs 中的 YAP1 可能是改善肺再生的新干预措施。
