Characterization of TGFB-Dependent Mechanoresponses by Aortic Smooth Muscle Cells

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 提示TAAs是细胞机械传感和机械调节功能受损的结果。 赋予主动脉壁结构完整性的细胞外基质。重要的是，可以查看转化生长因子β 部分，作为一种重要的机械换能器，其产生和激活是机械敏感的，其 下游基因产物包括可收缩的蛋白质，这些蛋白质对感觉和 调节细胞外基质的产生，以响应其增加的信号。 我们的工作目标是测试关于结构和教学角色之间相互作用的新假设 转化生长因子β信号改变，血管平滑肌细胞对改变的壁应力的机械感觉(特别是由于 高血压，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。具体来说， 我们将表征胸主动脉中的平滑肌细胞对增加的壁应力和 破坏依赖转化生长因子β信号的纤维蛋白-1，并导致主动脉壁不适应性重塑。这个 因此，我们的工作结果将为转化生长因子β信号在血管内皮细胞瘤中的作用提供第一个机制研究。 高血压(TAAS的主要危险因素)和细胞外基质受损(纤维蛋白-1，导致 大多数症状性TAA)，同时首次测试最近提出的功能失调的假说 平滑肌对基质的机械感知和机械调节是许多不同原因的TAAS的基础。在……里面 特别是，我们认为，如果平滑肌细胞感觉到的应力低于 动态平衡，即使在实际应力正常或高于正常的情况下也是如此，这将驱动墙 向动脉瘤化发展。血管平滑肌对转化生长因子β依赖性机械反应的表征 肌肉细胞可能识别新的分子靶点来治疗TAAS，这是一种没有电流的致命疾病 药物疗法。

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 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 an important 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 our work 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. Specifically, we will characterize responses of smooth muscle cells in the thoracic aorta to increased wall stresses and disrupted fibrillin-1 that depend on TGFβ signaling and lead to maladaptive remodeling of the aortic wall. The results of our work will thereby provide the first mechanistic investigation of roles of TGFβ signaling in cases of hypertension (a major risk factor for TAAs) and compromised extracellular matrix (fibrillin-1, the cause of the majority of syndromic TAAs) while testing, for the first time, the recently proposed hypothesis that dysfunctional smooth muscle mechanosensing and mechanoregulation of matrix underlies many different causes of TAAs. In particular, we suggest that smooth muscle cells will invoke an atrophic process if they sense stresses lower than homeostatic even in cases wherein the actual stress is normal or higher than normal, which will drive the wall toward aneurysmal development. The characterization of TGFβ-dependent mechanoresponses by aortic smooth muscle cells may identify new molecular targets to treat TAAs, a lethal disease and without current pharmacotherapy.