Department of Biomedical Engineering, Yale University, New Haven, CT, United States of America.
PLoS Comput Biol. 2020 Oct 20;16(10):e1008273. doi: 10.1371/journal.pcbi.1008273. eCollection 2020 Oct.
Myriad risk factors-including uncontrolled hypertension, aging, and diverse genetic mutations-contribute to the development and enlargement of thoracic aortic aneurysms. Detailed analyses of clinical data and longitudinal studies of murine models continue to provide insight into the natural history of these potentially lethal conditions. Yet, because of the co-existence of multiple risk factors in most cases, it has been difficult to isolate individual effects of the many different factors or to understand how they act in combination. In this paper, we use a data-informed computational model of the initiation and progression of thoracic aortic aneurysms to contrast key predisposing risk factors both in isolation and in combination; these factors include localized losses of elastic fiber integrity, aberrant collagen remodeling, reduced smooth muscle contractility, and dysfunctional mechanosensing or mechanoregulation of extracellular matrix along with superimposed hypertension and aortic aging. In most cases, mild-to-severe localized losses in cellular function or matrix integrity give rise to varying degrees of local dilatations of the thoracic aorta, with enlargement typically exacerbated in cases wherein predisposing risk factors co-exist. The simulations suggest, for the first time, that effects of compromised smooth muscle contractility are more important in terms of dysfunctional mechanosensing and mechanoregulation of matrix than in vessel-level control of diameter and, furthermore, that dysfunctional mechanobiological control can yield lesions comparable to those in cases of compromised elastic fiber integrity. Particularly concerning, therefore, is that loss of constituents such as fibrillin-1, as in Marfan syndrome, can compromise both elastic fiber integrity and mechanosensing.
多种风险因素——包括不受控制的高血压、衰老和多种基因突变——导致胸主动脉瘤的发生和扩大。对临床数据的详细分析和对小鼠模型的纵向研究继续提供对这些潜在致命疾病自然史的深入了解。然而，由于大多数情况下存在多种风险因素并存，因此很难单独分离出许多不同因素的个别影响，也很难理解它们如何共同作用。在本文中，我们使用一个关于胸主动脉瘤发生和进展的基于数据的计算模型来对比孤立和组合的关键易患风险因素；这些因素包括弹性纤维完整性的局部丧失、异常的胶原重塑、平滑肌收缩性降低以及细胞外基质的功能失调的机械感知或机械调节，以及叠加的高血压和主动脉老化。在大多数情况下，细胞功能或基质完整性的轻度至重度局部丧失会导致胸主动脉的不同程度的局部扩张，在易患风险因素共存的情况下，扩张通常会加剧。模拟结果首次表明，在基质的功能失调的机械感知和机械调节方面，平滑肌收缩功能障碍的影响比血管直径的控制更为重要，而且，功能失调的机械生物学控制可以产生与弹性纤维完整性受损病例相当的病变。因此，特别令人担忧的是，诸如弹性蛋白纤维完整性和机械感知等组成部分的丧失，如马凡综合征，会损害弹性纤维完整性和机械感知。
