Mechanosensitive mechanism of age-dependent decline in angiogenesis in the lung

肺血管生成年龄依赖性下降的机械敏感机制

• 批准号: 9906834
• 负责人: TADANORI MAMMOTO
• 金额: $ 19万
• 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: 2019-04-15 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906834
• 关键词: Adult; Aging; Angiopoietins; Animals; Apoptosis; Attenuated; Biophysics; Blood Vessels; Blood capillaries; Cell Nucleus; Cell Proliferation; Cell Shape; Cell Size; Chemicals; Chronic Obstructive Airway Disease; Chronic lung disease; Cultured Cells; Cytoskeleton; Data; Development; Endothelial Cells; Extracellular Matrix; Fibrin; Fibronectins; Gel; Gene Expression; Geometry; Glycine decarboxylase; Goals; Growth Factor; Impairment; Implant; In Vitro; Island; Knowledge; Lead; Lung; Mediating; Morphogenesis; Mus; Natural regeneration; Neonatal; Nuclear Protein; Organ; Pathogenesis; Play; Printing; Proteins; Reporting; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Signaling Protein; Structure; System; Tissues; Transcription Coactivator; Work; age effect; age related; aged; angiogenesis; cell behavior; cell growth; clinically relevant; in vitro activity; innovation; knock-down; lung development; lung regeneration; lung repair; mechanical force; organ growth; organ regeneration; protein expression; repaired; senescence

Project Summary Age-dependent impairment of lung regeneration and repair contributes to the pathogenesis of aging- associated chronic lung diseases (CLD). Angiogenesis – the formation of new blood capillaries- plays a key role in lung regeneration and is impaired in aging animals. Thus, in order to develop more efficient therapies for aging-associated CLD, we need to understand the mechanisms by which aging impairs angiogenesis in the lung. In addition to soluble growth factors and signaling molecules, biophysical factors alter angiogenic gene expression and regulate angiogenesis. We have reported that changes in cell size and geometry control endothelial cell (EC) growth. It is known that cell size increases during aging in various tissues. However, the effects of age-dependent increases in EC size on impairment of angiogenesis in the aged lung and the underlying mechanism have not been explored. The overall goal of this proposal is to characterize the mechanosensitive mechanism of age-dependent decline in angiogenesis, and to leverage this knowledge to develop an efficient strategy for CLD. Angiopoietin (Ang)-Tie2 signaling controls angiogenesis and plays important roles in lung development and regeneration. The mechanosensitive transcriptional co-activator, Yes- associated protein (YAP1), senses various mechanical forces and controls organ development and regeneration. YAP1 stimulates angiogenesis through angiopoietin2 (Ang2) signaling and deregulation of YAP1 is involved in the pathogenesis of aging-associated CLD. Our new preliminary data demonstrate that pulmonary ECs in aged mice are significantly larger than those in young mice. The levels of YAP1 are lower and EC proliferation is inhibited in ECs isolated from aged mouse lungs compared to those from younger mouse lungs. YAP1 knockdown decreases Ang2 expression in mouse lung ECs and the levels of Ang2 is lower in aged mouse lung ECs. When we culture aged lung ECs on single-cell sized fibronectin-coated large islands comparable in size to aged mouse lung EC, YAP1 is excluded from the nucleus and is inactive, while reduction of aged EC size restores YAP1 nuclear localization. Vascular network formation is inhibited in the fibrin gel implanted on the aged mouse lungs. We hypothesize that age-dependent increases in EC size may suppress aged EC proliferation and angiogenesis in the aged mouse lung through aberrant YAP1-Ang2 signaling. In Aim1, we will investigate the effects of age-dependent changes in EC size on EC proliferation, apoptosis, and senescence using the microcontact printing system. In Aim2, we will determine whether EC size-dependent changes in YAP1 signaling mediates impairment of angiogenesis in the aged lung through Ang2. Our idea to focus on the effects of age-related changes in EC size on angiogenesis is highly unique and innovative advances. If this study proves that reduction of aged EC size reverses the age-dependent decline in vascular morphogenesis in the aged lungs through YAP1 signaling, this work holds considerable promise to lead to the development of new and better strategies for aging-associated CLD.

项目摘要 年龄相关性肺再生和修复功能障碍参与了衰老的发病机制。 相关慢性肺部疾病(CLD)。血管生成--新的毛细血管的形成--起着关键作用 在肺再生中的作用，在衰老的动物中受到损害。因此，为了开发更有效的治疗方法 衰老相关的CLD，我们需要了解衰老损害血管生成的机制 阿龙。除了可溶的生长因子和信号分子外，生物物理因子还改变血管生成基因 表达和调节血管生成。我们已经报告了细胞大小和几何控制的变化 内皮细胞(EC)生长。众所周知，在各种组织中，细胞尺寸在老化过程中增大。然而， 增龄相关内皮细胞大小增加对老年肺血管生成障碍的影响 潜在的机制还没有被探索出来。这项提案的总体目标是将 年龄依赖性血管生成下降的机械敏感机制，并利用这一知识来 为CLD制定有效的策略。血管生成素(Ang)-Tie2信号调控血管生成及其作用 在肺发育和再生中发挥重要作用。机械敏感型转录共激活因子，是的- 相关蛋白(YAP1)，感受各种机械力，控制器官发育和 再生。YAP1通过血管生成素2(Ang2)信号转导和解除YAP1的调控促进血管生成 参与了增龄性CLD的发病机制。我们新的初步数据表明 老年小鼠肺内皮细胞明显大于青年小鼠。YAP1的水平较低 与年轻小鼠肺内皮细胞相比，老年小鼠肺内皮细胞的增殖受到抑制 小鼠的肺。YAP1基因敲除可降低小鼠肺内皮细胞Ang2的表达 衰老小鼠肺内皮细胞数量减少。当我们在单细胞大小的纤维连接蛋白包被的大细胞上培养老化的肺内皮细胞时 岛的大小与衰老的小鼠肺内皮细胞相当，YAP1被排除在细胞核之外，处于非活动状态，而 老化EC大小的减少恢复了YAP1的核定位。血管网络的形成受到抑制 将纤维蛋白凝胶植入老龄小鼠肺内。我们假设EC大小与年龄相关的增长可能 YAP1-Ang2基因异常抑制衰老小鼠肺内皮细胞增殖和血管生成 发信号。在Aim1中，我们将研究EC大小随年龄变化对EC增殖的影响。 使用微接触打印系统进行细胞凋亡和衰老。在AIM2中，我们将确定EC是否 YAP1信号的大小依赖变化通过以下途径介导老年肺血管生成障碍 ANG2。我们关注与年龄相关的内皮细胞大小变化对血管生成的影响的想法是非常独特的 创新进步。如果这项研究证明老年EC大小的减少逆转了年龄相关性的下降 通过YAP1信号在老年肺中的血管形态发生，这项工作有相当大的希望 导致制定新的、更好的应对与衰老相关的慢性阻塞性肺病的战略。