Smooth Muscle Cell AT1a Receptor in Initiating Events in AAAs

我们提出一个中心假设，即Ang11通过血管紧张素转换酶AT1受体启动AAA的形成 激活调节LRP-uPAR轴以促进中层巨噬细胞聚集。为了测试这一点 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AT1a受体对AAA的产生和主动脉中细胞的变化。平滑的效果 肌细胞特异性AT1a受体缺陷对AAA发育的影响将在注射Ang11的低密度脂蛋白中确定 受体/-小鼠。我们将使用AT1a受体漂浮的小鼠，在这些小鼠中，平滑肌细胞将出现缺陷 在SM22的控制下表达Cre。血管紧张素转换酶1a在血管内皮细胞中的作用 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：研究血管紧张素转换酶11在血管内皮细胞LRP调节中的作用及作用 降低LRP对AAA发展的易感性。我们将确定Angll通过的机制 下调LRP的表达。这将在来自特定主动脉的培养的平滑肌细胞中进行。 地区。我们将确定LRP基因亚型的小鼠是否更容易受到Ang11诱导 AAAS。这将在缺乏RAP的小鼠身上进行，RAP是LRP的分子伴侣。目标3： 确定uPAR在血管紧张素转换酶诱导的AAA形成中的作用。我们将使用uPAR-/-老鼠 探讨其在血管紧张素转换酶诱导的腹主动脉硬化中的作用。“正向”与“反向”骨髓 移植研究将确定与Ang11诱导的AAA有关的uPAR的组织位点。目标4： 确定血管内膜巨噬细胞在血管内注射过程中聚集的来源。骨髓 表达CD45等位基因变体的小鼠的转移研究将被用来确定Ang11是否诱导了 巨噬细胞在主动脉层的积聚来源于血液中的单核细胞或居留者 主动脉外膜内的巨噬细胞。

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.