The role of YAP1 in angiogenesis during organ regeneration

YAP1在器官再生过程中血管生成中的作用

• 批准号: 10444922
• 负责人: TADANORI MAMMOTO
• 金额: $ 38.01万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10444922
• 关键词: Adult; Alveolar; Angiogenesis Inhibition; Angiogenic Factor; Attenuated; Binding; Blood Vessels; Blood capillaries; Cardiac; Cardiac Output; Clinical; Data; Development; Endothelial Cells; Endothelium; Environment; Fibrin; Gel; Genes; Goals; Growth; Human; Impairment; Implant; In Vitro; Injury; Knock-out; Knowledge; Lead; Left; Ligation; Lobar; Lobe; Lung; Mechanics; Mediating; Modeling; Molecular; Morphogenesis; Mus; Natural regeneration; Organ; Organ Size; Perfusion; Play; Pneumonectomy; Prosthesis; Proteins; Pulmonary artery structure; Reporting; Retina; Role; Scientific Advances and Accomplishments; Signal Transduction; Silicones; Stretching; Structure; System; Tamoxifen; Transcription Coactivator; Transgenic Mice; Work; angiogenesis; blood vessel development; cadherin 5; density; implantation; innovation; knock-down; lung lobe; mechanical force; novel; organ growth; organ regeneration; prevent; protein activation; receptor; recruit; regenerative; repaired; shear stress; stem cells; transcription factor

Project Summary: Angiogenesis – the formation of new blood capillaries - plays a key role in organ regeneration. Thus, in order to regenerate adult organs, we need to understand the mechanisms of angiogenesis during organ regeneration. It has been reported that adult human lungs have potential to grow after unilateral pneumonectomy (PNX) and that inhibition of angiogenesis impairs post-PNX lung growth in adult mice. The overall goal of this proposal is to characterize the mechanism of angiogenesis during organ regeneration using lung as a model and leverage this knowledge to develop an efficient strategy for organ regeneration. Mechanosensitive transcriptional co- activators, Yes-associated protein (YAP1) and transcriptional co-activator with PDZ-binding motif (TAZ), stimulate angiogenesis and control organ size and regeneration. In the lung, YAP1 activation in alveolar stem cells promotes post-PNX lung growth. However, the role of endothelial YAP1/TAZ in angiogenesis during post- PNX lung growth remains unclear. Our preliminary data demonstrate that knockdown of YAP1 and/or TAZ decreases the expression of angiogenic factor receptor, Tie2, in endothelial cells (ECs) and inhibits EC sprouting. After unilateral PNX, the expression of YAP1/TAZ and Tie2 and vascular density increased in the remaining lung lobes. Compensatory lung growth after PNX was inhibited in VE-cadherin-specific Yap1 and/or Taz knockout (Yap1fl/fl-Cdh5CreERT2, Yap1iΔEC, Taz iΔEC, or Yap1/TaziΔEC) mice after tamoxifen-induced Yap1/Taz deletion. When we implanted fibrin gel on the control Yap1fl/fl mouse lung, ECs were recruited from host lungs and made vascular networks in the implanted gels, while vascular formation was attenuated in the gel implanted on the Yap1fl/fl-Cdh5CreERT2 mouse lungs. Parenchymal stretch and increases in microvascular perfusion and shear stress after unilateral PNX contribute to post-PNX lung growth. Insertion of silicone prosthesis to replace an excised lobe prevented post-PNX lung growth and decreased YAP1/TAZ expression. Ligation of right cardiac lobe pulmonary artery stimulated lung growth of the remaining non-occluded lobes after left PNX. We hypothesize that angiogenesis is stimulated during compensatory lung growth after PNX through mechanosensitive endothelial YAP1/TAZ signaling. In Aim 1, we will investigate the mechanism by which endothelial YAP1/TAZ control angiogenic signaling during post-PNX lung growth in vitro. In Aim 2, we will determine whether endothelial YAP1/TAZ control blood vessel formation during post-PNX lung growth in the mouse lung. In Aim 3, we will investigate the effects of mechanical environment altered by PNX on blood vessel formation in the mouse lung. Our focus on the new mechanosensitive mechanism of angiogenesis during post-PNX lung growth and the novel mouse lung gel implantation system are highly unique and innovative scientific advances. If this study validates that endothelial YAP1/TAZ stimulate angiogenesis in the mouse lungs after PNX, this work will further our understanding of the mechanism of angiogenesis and lead to the development of new and better strategies for organ regeneration.

项目概要： 血管生成——新毛细血管的形成——在器官再生中起着关键作用。 再生成人器官，我们需要了解器官再生过程中血管生成的机制。 据报道，成年人的肺部在单侧肺切除术（PNX）和 抑制血管生成会损害成年小鼠 PNX 后的肺部生长 该提案的总体目标是。 使用肺作为模型和杠杆来表征器官再生过程中血管生成的机制 这些知识可用于开发器官再生的有效策略。 激活剂、Yes 相关蛋白 (YAP1) 和具有 PDZ 结合基序 (TAZ) 的转录共激活剂， 刺激血管生成并控制器官大小和再生 在肺中，YAP1 在肺泡干中激活。 然而，内皮 YAP1/TAZ 在 PNX 后血管生成中的作用。 PNX 肺部生长仍不清楚。我们的初步数据表明 YAP1 和/或 TAZ 的敲低。 降低内皮细胞 (EC) 中血管生成因子受体 Tie2 的表达并抑制 EC 单侧PNX后，YAP1/TAZ和Tie2的表达以及血管密度增加。 VE-钙粘蛋白特异性 Yap1 和/或 PNX 后剩余肺叶的代偿性生长。 他莫昔芬诱导后 Taz 敲除（Yap1fl/fl-Cdh5CreERT2、Yap1iΔEC、Taz iΔEC 或 Yap1/TaziΔEC）小鼠 当我们将纤维蛋白凝胶植入对照 Yap1fl/fl 小鼠肺中时，从 Yap1/Taz 缺失中招募 ECs。 宿主肺部并在植入的凝胶中形成血管网络，而血管形成在植入的凝胶中减弱 凝胶植入 Yap1fl/fl-Cdh5CreERT2 小鼠肺实质拉伸并增加微血管。 单侧 PNX 后的灌注和剪切应力有助于 PNX 后肺部的生长。 替换切除肺叶的假体可阻止 PNX 后肺生长并降低 YAP1/TAZ 表达。 右心叶肺动脉的结扎刺激了剩余未闭塞肺叶的肺生长 离开 PNX 后，我们勇敢地说，PNX 后的代偿性肺部生长会刺激血管生成。 在目标 1 中，我们将通过机械敏感内皮 YAP1/TAZ 信号传导来研究其机制。 在目标 2 中，内皮 YAP1/TAZ 在 PNX 后肺生长过程中控制血管生成信号传导。 将确定内皮 YAP1/TAZ 是否在 PNX 后肺生长过程中控制血管形成 在目标 3 中，我们将研究 PNX 改变的机械环境对血液的影响。 小鼠肺中的血管形成我们关注血管生成的新机械敏感机制。 在 PNX 后肺部生长过程中，新型小鼠肺凝胶植入系统非常独特， 如果这项研究证实内皮 YAP1/TAZ 可以刺激血管生成，那么这是创新性的科学进展。 PNX 后的小鼠肺部，这项工作将进一步我们对血管生成机制的理解，并导致 制定新的更好的器官再生策略。