Smooth muscle cell deletion of low-density lipoprotein receptor-related protein 1 augments angiotensin II-induced superior mesenteric arterial and ascending aortic aneurysms.
Smooth muscle cell deletion of low-density lipoprotein receptor-related protein 1 augments angiotensin II-induced superior mesenteric arterial and ascending aortic aneurysms.
复制标题
DOI：
10.1161/atvbaha.114.304683
复制
发表时间：
2015-01
期刊：
影响因子：
--
通讯作者：
Daugherty A
中科院分区：
文献类型：
--
作者：
Davis FM;Rateri DL;Balakrishnan A;Howatt DA;Strickland DK;Muratoglu SC;Haggerty CM;Fornwalt BK;Cassis LA;Daugherty A
LRP1是一种参与内吞作用和细胞信号通路的多功能蛋白，当在血管平滑肌细胞（SMCs）中缺失时，会导致一系列血管病变。本研究的目的是确定SMCs中LRP1缺失是否影响血管损伤引起的动脉病变。LRP1蛋白丰度在选定的动脉区域是相同的，但smc特异性LRP1的消耗对年轻小鼠的腹主动脉和升主动脉直径没有影响。为了确定LRP1缺乏对AngII血管反应的影响，smc特异性LRP1 (smLRP1) +/+和-/-小鼠注入生理盐水、AngII或去甲肾上腺素（NE）。几只smLRP-/-小鼠在AngII输注期间死于肠系膜上动脉（SMA）破裂。在存活小鼠中，AngII显著增强了smLRP1-/-小鼠的SMA扩张。在NE输注期间，类似的反应证明了SMA扩张是血压依赖性的。SMA的扩张也与巨噬细胞的大量积累有关，但弹性蛋白的碎片化很小。AngII输注导致smLRP1+/+和-/-小鼠腹主动脉直径无显著差异。相比之下，血管灌注的smLRP1-/-小鼠升主动脉扩张明显加剧，但NE对主动脉区和主动脉区均无显著影响。注射AngII后，smLRP1-/-小鼠升主动脉巨噬细胞积累最小，但弹性蛋白断裂和LRP1配体MMP-2、uPA等mRNA丰度显著增加。smLRP1缺乏对血管诱导的腹主动脉瘤形成无影响。相反，smLRP1-/-小鼠的AngII输注加重了SMA和升主动脉扩张。这两个区域的扩张与血压和不同的病理特征有不同的关联。
LRP1, a multifunctional protein involved in endocytosis and cell signaling pathways, leads to a range of vascular pathologies when deleted in vascular smooth muscle cells (SMCs). The purpose of this study was to determine whether LRP1 deletion in SMCs influenced AngII-induced arterial pathologies. LRP1 protein abundance was equivalent in selected arterial-regions, but SMC-specific LRP1 depletion had no effect on abdominal and ascending aortic diameters in young mice. To determine the effects of LRP1 deficiency on AngII vascular responses, SMC-specific LRP1 (smLRP1) +/+ and -/- mice were infused with saline, AngII, or norepinephrine (NE). Several smLRP-/- mice died of superior mesenteric arterial (SMA) rupture during AngII infusion. In surviving mice, AngII profoundly augmented SMA dilation in smLRP1-/- mice. SMA dilation was blood pressure-dependent as demonstrated by a similar response during NE infusion. SMA dilation was also associated with profound macrophage accumulation, but minimal elastin fragmentation. AngII infusion led to no significant differences in abdominal aorta diameters between smLRP1+/+ and -/- mice. In contrast, ascending aortic dilation was exacerbated markedly in AngII-infused smLRP1-/- mice, but NE had no significant effect on either aortic region. Ascending aortas of smLRP1-/- mice infused with AngII had minimal macrophage accumulation but significantly increased elastin fragmentation and mRNA abundance of several LRP1 ligands including MMP-2 and uPA. smLRP1 deficiency had no effect on AngII-induced abdominal aortic aneurysm formation. Conversely, AngII infusion in smLRP1-/- mice exacerbated SMA and ascending aorta dilation. Dilation in these two regions had differential association with blood pressure and divergent pathologic characteristics.