Developmental Basis of Aneurysm in Marfan Syndrome and Therapeutic Implication

马凡综合征(MFS)是一种常见的疾病，由编码基质蛋白纤维蛋白-1的基因突变引起。我们先前的工作表明，MFS的许多表现，包括主动脉瘤、瓣膜疾病、肺气肿和骨骼肌病，都是由生长因子β家族的过度激活和信号传递引起的，在小鼠模型中可以被TGFβ阻断而减弱。流行的观点认为，由于细胞外环境的改变，MFS表现出“正常”细胞的异常行为。我们现在提出的证据表明，成年MFS小鼠的主动脉壁内存在“异常”细胞，在早期发育过程中，由于一种称为内皮细胞到间充质细胞的转变(EnMT)，这些细胞在身份和特征上经历了TGFbeta依赖的永久性转变。转化后的肌成纤维细胞表现出许多有害行为，包括高转化生长因子β信号、血管紧张素II(Ang11)依赖的纤维化和基质降解酶的高表达。这项工作中要检验的主要假设是，EnMT来源的细胞推动疾病的进展，并且EnMT在疾病状态下出生后继续填充在升主动脉中。利用小鼠模型，我们将确定在纤维蛋白-1缺乏的小鼠的主动脉中驱动EnMT的途径，并将纯化EnMT衍生的细胞，从而能够识别它们的有害行为并探索驯服它们的策略。目前，我们可以设想至少9种不同的治疗药物，从理论上防止正在进行的EnMT和/或调节治疗开始时驻留在主动脉壁内的肌成纤维细胞的非生产性性能。这些将在MFS的遗传定义和验证的小鼠模型中进行测试。值得注意的是，这些药物中的一些已经在临床上用于其他适应症，这表明快速翻译到MFS患者的可能性。我们目前的数据表明，在MFS中，明显获得性迟发性表型的前置细胞识别存在发育强加的固定改变，这一范式代表了一种关于遗传易感性的新思维方式，有助于阐明治疗的局限性和机会，并可能被证明与其他疾病相关。

Marfan syndrome (MFS) is a common disorder caused by mutations in the gene encoding the matrix protein fibrillin-1. Our prior work has shown that many manifestations of MFS, including aortic aneurysm, valve disease, emphysema and skeletal muscle myopathy, are caused by excessive activation of and signaling by the TGF beta family of growth factors and can be attenuated by TGFbeta blockade in mouse models. The prevailing view has been that MFS manifests abnormal behaviors of "normal" cells due to alterations in their extracellular environment. We now present evidence for "abnormal" cells within the aortic wall of adult MFS mice that have undergone a TGFbeta-dependent permanent transition in identity and character during early development due to a process termed endothelial-to-mesenchymal transition (EnMT). After transition, resulting myofibroblasts exhibit many deleterious behaviors including high TGFbeta signaling, angiotensin II (Angll)-dependent fibrosis, and high expression of matrix-degrading enzymes. The major hypotheses to be tested in this work are that EnMT-derived cells drive progression of disease and that EnMT continues to populate the ascending aorta during postnatal life in disease states. Using mouse models, we will determine the pathways that drive EnMT in the aorta of fibrillin-1 deficient mice and will purify EnMT-derived cells, allowing identification of their deleterious behaviors and exploration of strategies to tame them. Currently, we can envision at least 9 different therapeutic agents that will theoretically prevent ongoing EnMT and/or modulate the nonproductive performance of myofibroblasts resident within the aortic wall at the time of initiation of treatment. These will be tested in genetically defined and validated mouse models of MFS. Remarkably, a number of these agents are already in clinical use for other indications, suggesting the potential for rapid translation to people with MFS. Our current data suggest a developmentally-imposed fixed alteration in cellular identify in the prediposition for apparently acquired late-onset phenotypes in MFS, This paradigm represents a novel way of thinking about genetic predisposition, aids in the elucidation of therapeutic limitations and opportunities, and will likely prove relevant to other conditions.