Insights on the Pathogenesis of Aneurysm through the Study of Hereditary Aortopathies.
Insights on the Pathogenesis of Aneurysm through the Study of Hereditary Aortopathies.
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DOI：
10.3390/genes12020183
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发表时间：
2021-01-27
期刊：
影响因子：
3.5
通讯作者：
MacFarlane EG
中科院分区：
文献类型：
--
作者：
Creamer TJ;Bramel EE;MacFarlane EG
胸主动脉瘤（TAA）是主动脉的永久性和局部扩张，使患者易发生危及生命的主动脉夹层或破裂风险。导致遗传性TAA的致病性变异的鉴定描绘了维持主动脉稳态所需的基本分子过程。血管平滑肌细胞（VSMCs）精心制作和重塑细胞外基质（ECM），以响应来自其环境的机械和生化线索。遗传性动脉瘤的病因变异损害了参与这些信号传递或解释的基因产物的功能，启动了最终导致血管变性和机械故障的过程。这些突变包括干扰刺激物通过整合素从基质到肌动蛋白-肌球蛋白细胞骨架的转导的突变，以及损害由转化生长因子-β（TGF-β）激活的信号传导途径的突变。在这篇综述中，我们总结了健康主动脉壁的特点，参与VSMC表型调制的主要途径，以及TAA相关突变损害的基本分子功能。我们还讨论了如何异质性和平衡的适应性和适应不良反应的初始遗传侮辱可能有助于疾病。
Thoracic aortic aneurysms (TAA) are permanent and localized dilations of the aorta that predispose patients to a life-threatening risk of aortic dissection or rupture. The identification of pathogenic variants that cause hereditary forms of TAA has delineated fundamental molecular processes required to maintain aortic homeostasis. Vascular smooth muscle cells (VSMCs) elaborate and remodel the extracellular matrix (ECM) in response to mechanical and biochemical cues from their environment. Causal variants for hereditary forms of aneurysm compromise the function of gene products involved in the transmission or interpretation of these signals, initiating processes that eventually lead to degeneration and mechanical failure of the vessel. These include mutations that interfere with transduction of stimuli from the matrix to the actin–myosin cytoskeleton through integrins, and those that impair signaling pathways activated by transforming growth factor-β (TGF-β). In this review, we summarize the features of the healthy aortic wall, the major pathways involved in the modulation of VSMC phenotypes, and the basic molecular functions impaired by TAA-associated mutations. We also discuss how the heterogeneity and balance of adaptive and maladaptive responses to the initial genetic insult might contribute to disease.
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