TGFB-Dependent Mechanoresponses by Aortic Smooth Muscle Cells Govern Aneurysms

项目总结 胸主动脉瘤(TAA)影响青年和老年男性和女性，并负责显着 发病率和死亡率。最近几年的研究结果表明，异常的活动或信号通过 转化生长因子-β(转化生长因子-ββ)在动脉粥样硬化中起着重要作用，但关于转化生长因子-β在动脉粥样硬化中的作用仍存在争议。 精密机械装置。这种理解的缺乏继续阻碍了对改善治疗方法的确认 最近一项备受期待的血管紧张素Ⅱ类药物氯沙坦临床试验失败所揭示的方法 受体拮抗剂。我们和其他人最近假设，易感基因突变的集合 这表明，TAAs的部分结果是受损的细胞机械传感和机械调节 赋予主动脉壁结构完整性的细胞外基质。重要的是，转化生长因子β可以 在一定程度上，它被视为一种关键的机械换能器--它的产生和激活是机械敏感的 它的下游基因产物包括对感觉至关重要的收缩蛋白。 以及调节细胞外基质，以响应其增加的信号。 这个项目的目标是测试关于结构角色和教学角色之间相互作用的新假设 转化生长因子β信号的改变，心肌细胞对改变的壁应力的机械感知(特别是 高血压是TAAS的主要危险因素)，以及纤维蛋白-1的完整性，这是一种基本的糖蛋白， 与弹性蛋白结合形成弹性纤维。为此，我们将使用新的基因组合 改良的小鼠模型、体内诱发性高血压模型和TAAs的临床标本。我们会 描述胸主动脉中的平滑肌细胞对增加的壁应力的反应(通过计算 核心C)和依赖于转化生长因子β信号的纤维蛋白-1被破坏，并导致适应性不良的血管重塑 主动脉壁。最后，这个项目将自然补充这个PPG中的其他3个项目。我们的结果是 工作(项目4)将扩展细胞外基质完整性分级损失如何影响的表征 TAAs对生理血流动力学的生物学反应，包括血管紧张素受体信号转导 载荷(项目1)，将补充控制激活的生物力学机制的研究 转化生长因子β在动脉粥样硬化中的作用(项目2)，并将为内皮细胞血流调节反应和细胞外的研究提供信息 动脉粥样硬化中的基质重塑(项目3)。正如在其他三个项目中一样，我们将使用核心B来阐明复杂 所研究的机械、结构和生物因素之间的系统级别的相互作用。通过以下方式协调 核心A，这一高度集成的PPG的发现将大大有助于理解 主动脉细胞机械感知功能障碍和寻找治疗TAAs的新分子靶点。

PROJECT SUMMARY Thoracic aortic aneurysms (TAAs) affect young and old males and females and are responsible for significant morbidity and mortality. Findings over recent years suggest that an aberrant activity of or signaling through transforming growth factor-beta (TGFβ) plays important roles in TAAs, yet controversy remains regarding the precise mechanisms. This lack of understanding continues to hinder the identification of improved therapeutic approaches as revealed by the recent failure of a highly anticipated clinical trial of losartan, an angiotensin-II receptor antagonist. We and others recently hypothesized that the collection of predisposing genetic mutations suggests that TAAs result, in part, from a compromised cellular mechanosensing and mechanoregulation of the extracellular matrix that endows the aortic wall with its structural integrity. Importantly, TGFβ can be viewed, in part, as a critical mechanotransducer – its production and activation are mechanosensitive and its downstream gene products include the contractile proteins that are fundamental to sensing and regulating the extracellular matrix that is produced in response to its increased signaling. The goal of this project is to test novel hypotheses on interactions among the structural and instructional roles of altered TGFβ signaling, smooth muscle cell mechanosensing of altered wall stresses (particularly those due to hypertension, a primary risk factor for TAAs), and the integrity of fibrillin-1, an essential glycoprotein that associates with elastin to form elastic fibers. Towards this end, we will use a combination of new genetically modified mouse models, in vivo models of induced hypertension, and clinical specimens of TAAs. We will characterize responses of smooth muscle cells in the thoracic aorta to increased wall stresses (computed by Core C) and disrupted fibrillin-1 that depend on TGFβ signaling and lead to maladaptive remodeling of the aortic wall. Finally, this project will complement naturally the other 3 projects in this PPG. The results of our work (Project 4) will extend the characterization of how graded losses of extracellular matrix integrity influence the biological responses, including angiotensin receptor signaling, of TAAs to physiological hemodynamic loads (Project 1), will complement investigations of biomechanical mechanisms that control the activation of TGFβ in TAAs (Project 2), and will inform studies of endothelial flow-regulated responses and extracellular matrix remodeling in TAAs (Project 3). As in the other three projects, we will use Core B to elucidate complex systems-level interactions among the mechanical, structural, and biological factors studied. Coordinated via Core A, the findings of this highly integrated PPG will contribute significantly to understanding coupled dysfunctional mechanosensing by aortic cells and identifying new molecular targets to treat TAAs.