Smooth Muscle Cell AT1a Receptor in Initiating Events in AAAs

我们提出了一个中心假设，即AngII通过平滑肌细胞AT 1受体启动AAA的形成 激活调节LRP-uPAR轴以促进中巨噬细胞积累。为了验证这一 假设，我们提出了以下具体目标：目标>1：确定平滑肌的贡献 细胞特异性AT 1a受体对AAA的产生和主动脉中的细胞变化。平滑的效果 将在AngII灌注的LDL中测定肌细胞特异性AT 1a受体缺陷对AAA发展的影响 受体-/-小鼠。我们将使用AT 1a受体floxed小鼠，其中平滑肌细胞缺陷将被称为 用在SM 22控制下表达的Cre完成。平滑肌细胞AT 1a的作用 受体缺陷将根据AAA起始阶段发生的细胞变化来确定 发展目的2：探讨血管紧张素Ⅱ对平滑肌细胞LRP的调节作用，以及血管紧张素Ⅱ对平滑肌细胞LRP表达的影响。 降低LRP对AAA发展的敏感性。我们将确定Angll 下调LRP。这将在来自特定主动脉的培养平滑肌细胞中进行。 地区我们将确定LRP亚型的小鼠是否更易受AngII诱导的细胞凋亡的影响。 AAA级。这将在缺乏RAP（LRP的分子伴侣）的小鼠中进行。目标3： 确定uPAR对AngII诱导的AAA的发展的贡献。我们将使用uPAR -/-小鼠 以确定其在AngII诱导的AAA的发展中的作用。“正向”与“反向”骨髓 移植研究将确定参与AngII诱导的AAA的uPAR的组织基因座。目标4： 确定AngII输注期间主动脉中积聚的中膜巨噬细胞的来源。骨髓 用表达CD 45等位基因变体的小鼠进行的转移研究将用于确定AngII诱导的CD 45表达是否与AngII诱导的CD 45表达有关。 巨噬细胞在主动脉层中的积聚来源于血液传播的单核细胞或驻留的巨噬细胞。 主动脉外膜中的巨噬细胞。

We propose a central hypothesis that Angll initiates AAA formation through smooth muscle cell AT1 receptor activation regulating the LRP-uPAR axis to promote medial macrophage accumulation. To test this hypothesis, we propose the following specific aims: Aim>1: Determine the contribution of smooth muscle cell-specific AT1a receptors to AAA production and cellular changes in the aorta. The effects of smooth muscle cell specific AT1a receptor deficiency on AAA development will be determined in Angll-infused LDL receptor -/- mice. We will use AT1a receptor floxed mice in which smooth muscle cell deficiency will be accomplished with Cre expressed under the control of SM22. The effect of smooth muscle cell AT1a receptor deficiency will be determined on the cellular changes that occur in the initiating phase of AAA development. Aim 2: Determine the role of Angll on regulation of LRP in smooth muscle cells and the effect of reduced LRP on susceptibility to AAA development. We will determine the mechanisms by which Angll downregulates LRP. This will be performed in cultured smooth muscle cells derived from specific aortic regions. We will determine if mice that are hypomorphic for LRP are more susceptible to Angll-induced AAAs. This will be performed in mice that are deficient in RAP, the molecular chaperone of LRP. Aim 3: Determine the contribution of uPAR to the development of Angll-induced AAAs. We will use uPAR -/- mice to determine its role in development of Angll-induced AAAs. "Forward" and "reverse" bone marrow transplantation studies will determine the tissue loci of uPAR involved in Angll-induced AAAs. Aim 4: Determine the origin of medial macrophages accumulated in the aorta during Angll-infusion. Bone marrow transfer studies with mice expressing allelic variants of CD45 will be used to define whether Angll-induced accumulation of macrophages in the aortic layers originate from blood-borne monocytes or resident macrophages in the adventitia of the aorta.