Vascular autophagy as a mediator of vascular aging and homeostasis

自噬在血管内稳态和血管反应性中的作用还知之甚少。在……里面 在这一建议中，我们描述了在内皮或平滑肌中缺乏自噬通量的小鼠 单元层。值得注意的是，抑制血管平滑肌细胞的自噬流量似乎 概述罕见的人类疾病Hutchinson-Gilford Progeria综合征(HGPS)的各个方面。 这种节段性早孕症是由层蛋白A/C基因的显性突变引起的。 虽然HGPS是一种加速衰老综合征，但大多数死亡是由血管引起的 并发症(如心肌梗塞和中风)。分析人类受试者以及 对小鼠疾病模型的表征，显示了大范围内的深刻变化 动脉。这些变化被认为是孕激素血管积聚的次要原因， 一种改变形式的层蛋白A，其产生在HGPS患者中受到青睐。有趣的是， 随着年龄的增长，孕激素也会在正常人的血管中积累。 因此，这些观察表明，从这一罕见的项目中吸取的教训 综合症，HGPS，可能有更广泛的应用。在本提案中，我们探讨了 自噬在HGPS节段性血管病变中的作用。使用各种新颖的鼠标 在血管壁中有条件地删除自噬的模型，以及人类 诱导多能干细胞(IPSCs)，其中的特定基因已通过CRISPR- 基于策略，我们建议研究受损之间的机械联系 自噬、HGPS病理和正常血管老化。因此，这些研究提供了第一个 血管内皮细胞和血管平滑肌细胞自噬如何调节的特性 血管动态平衡。

The role of autophagy in vascular homeostasis and vascular reactivity is poorly understood. In this proposal, we characterize mice lacking autophagic flux in the endothelial or smooth muscle cell layer. Remarkably, inhibiting autophagic flux in vascular smooth muscle cells appears to recapitulate aspects of the rare human disease Hutchinson-Gilford Progeria Syndrome (HGPS). This segmental progeriod condition is caused by a dominant mutation in the lamin A/C gene. While HGPS is an accelerated aging syndrome, most of the fatalities result from vascular complications (e.g. myocardial infarction and stroke). Analysis of human subjects, as well as characterization of mouse models of the disease, demonstrate profound changes in the large arteries. These changes are believed to be secondary to the vascular accumulation of progerin, an altered form of lamin A whose production is favored in patients with HGPS. Interestingly, progerin can also accumulate in the blood vessels of normal individuals as a function of aging. As such, these observations suggest that the lessons learned from this rare progeriod syndrome, HGPS, may have wider applications. In this proposal, we explore the role of autophagy in the segmental vascular pathology of HGPS. Using a variety of novel mouse models where autophagy has been conditionally deleted in the vessel wall, as well as human induced pluripotent stem cells (iPSCs) in which specific genes have been deleted via CRISPR- based strategies, we propose to study the mechanistic connection between impaired autophagy, HGPS pathology and normal vascular aging. As such, these studies provide the first characterization as to how endothelial and vascular smooth muscle cell autophagy regulates vascular homeostasis.