Vascular autophagy as a mediator of vascular aging and homeostasis

自噬在血管稳态和血管反应性中的作用知之甚少。在 这个提议，我们描述了缺乏内皮或平滑肌自噬通量的小鼠， 细胞层值得注意的是，抑制血管平滑肌细胞中的自噬流似乎 Hutchinson-Gilford早老症（HGPS）是一种罕见的人类疾病。 这种节段性早老性疾病是由核纤层蛋白A/C基因的显性突变引起的。 虽然HGPS是一种加速老化综合征，但大多数死亡是由血管性 并发症（如心肌梗死和中风）。分析人类受试者，以及 表征的小鼠模型的疾病，表现出深刻的变化，在大 动脉这些变化被认为是继发于早老蛋白的血管积累， 核纤层蛋白A的一种改变形式，其产生有利于HGPS患者。有趣的是， 早老蛋白也可以作为老化的函数在正常个体的血管中积累。 因此，这些观察表明，从这种罕见的早衰症中吸取的教训 HGPS可能有更广泛的应用。在本建议中，我们探讨了 自噬在HGPS节段性血管病理中的作用。使用多种新颖鼠标 在血管壁中自噬已经被有条件地删除的模型，以及人类 诱导多能干细胞（iPSC），其中特定基因已通过CRISPR删除- 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。这些研究提供了第一个 内皮细胞和血管平滑肌细胞自噬如何调节 血管稳态

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.