Fetal Basis of Dissecting Aortic Aneurysm

描述(申请人提供)：夹层主动脉瘤(DAA)是指主动脉内侧层突然撕裂或裂开，通常始于其胸部，并向远端延伸至其分支。DAA是马凡氏综合征中猝死的常见原因，也是一个孤立的事件，并与怀孕有关。在最近的实验中，我们发现，通过将计时怀孕大鼠(怀孕14-21天)暴露于无毒剂量的氨基脲，氨基脲是一种血管酶氨基脲敏感胺氧化酶(SSAO)的抑制剂，新生大鼠在出生后立即发展为典型的DAA。据我们所知，这是第一个环境诱导的发育性DAA的实验模型。我们假设，在发育过程中抑制SSAO会导致细胞产生关键的细胞外基质(结构)蛋白，特别是弹性蛋白复合体的生化、生物物理和遗传异常，从而导致血管壁的削弱。在这个新的实验模型中，我们将重点关注出生前一天的胎鼠，以揭示易患DAA的基质环境的变化。作为第一个特定目标，将定义主动脉结构组件中的生化异常。单个病理基质分子(例如，弹性蛋白复合体)的生物物理性质将使用令人兴奋的原子力显微镜新技术与正常进行比较。利用基因微阵列技术，DAA之前的基因改变将被揭示。然后，作为第二个特定目标，对来自同一胎鼠的血管平滑肌细胞进行机械实验，探索基因变化如何导致主动脉细胞外基质环境的变化，导致血管变弱和夹层。

DESCRIPTION (provided by applicant): Dissecting aortic aneurysm (DAA) is the sudden tearing or splitting of the medial layers of the aorta, usually beginning in its thoracic portion, and extending distally through its branches. A frequent cause of sudden death in Marfan's syndrome, DAA also occurs as an isolated event, and is associated with pregnancy. In recent experiments, we found that by exposing timed-pregnant rats (on days 14-21 of gestation) to nontoxic doses of semicarbazide, an inhibitor of the vascular enzyme semicarbazide-sensitive amine oxidase (SSAO), newborn rats develop classic DAA immediately after birth. To our knowledge, this is the first experimental model of environmentally induced, developmental DAA. We hypothesize that SSAO-inhibition during development results in biochemical, biophysical, and genetic aberrations in the cellular production of critical extracellular matriceal (structural) proteins, especially the elastin-complex, with resultant weakening of the vascular wall. In this new experimental model, we will focus on the fetal rat, the day before birth, to uncover the changes in matrix milieu that predispose to DAA. As a first Specific Aim, the biochemical aberrations in aortic structural components will be defined. Biophysical properties of single pathologic matrix molecules (e.g., elastin-complex) will be compared to normal using the exciting new technique of atomic-force-microscopy. With gene microarray techniques, genetic alterations that precede DAA will be revealed. Then, as a second Specific Aim, mechanistic experiments in vascular smooth muscle cells cultured from the same fetal rats will probe how genetic alterations drive the changes in aortic extracellular matrix milieu to result in vascular weakening, and dissection.