Constitutive expression of pregnancy-associated plasma protein-A in arterial smooth muscle reduces the vascular response to injury in vivo.
Constitutive expression of pregnancy-associated plasma protein-A in arterial smooth muscle reduces the vascular response to injury in vivo.
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DOI：
10.1152/ajpendo.00376.2012
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发表时间：
2013-01
期刊：
影响因子：
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通讯作者：
L. Bale;Zachary T. Resch;Sara L Harstad;M. Overgaard;C. Conover
中科院分区：
文献类型：
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作者：
L. Bale;Zachary T. Resch;Sara L Harstad;M. Overgaard;C. Conover
妊娠相关血浆蛋白-A（PAPP-A）的功能是增加局部IGF-I的生物活性。在这项研究中，我们使用的转基因小鼠组成型表达人PAPP-A的动脉平滑肌来测试的假设，PAPP-A的过度表达增强血管平滑肌细胞（SMC）的反应，IGF-I在体内。PAPP-A转基因（Tg）和野生型（WT）小鼠进行单侧颈动脉结扎，损伤诱导的SMC增生和新生内膜形成的模型。在WT和PAPP-A Tg小鼠中，内源性PAPP-A mRNA表达在颈动脉结扎后5天显示峰值升高。然而，在结扎后5天和10天，PAPP-A Tg小鼠的新生内膜比WT少70-75%，结扎动脉的闭塞显著减少。WT和PAPP-A Tg小鼠在结扎后中膜面积和血管重塑方面具有等同的增加。在WT或PAPP-A Tg小鼠的对侧颈动脉中，内侧区域几乎没有变化，并且没有新生内膜的证据。WT和PAPP-A Tg颈动脉均表现出SMC去分化的迹象，这先于导致新生内膜形成的增殖和迁移增加。然而，与WT相比，结扎的PAPP-A Tg动脉的中膜和新生内膜中增殖细胞的数量在术后第5天减少了90%。这种降低与IGF-I生物活性的体内标志物的显著降低和离体IGF-I刺激的受体磷酸化的降低相关。这些数据表明慢性（转基因）和瞬时（内源性）PAPP-A表达对血管损伤后新生内膜形成的不同影响，这可能部分归因于对IGF-I信号传导的不同影响。
Pregnancy-associated plasma protein-A (PAPP-A) functions to increase local IGF-I bioactivity. In this study, we used transgenic mice that constitutively express human PAPP-A in arterial smooth muscle to test the hypothesis that overexpression of PAPP-A enhances vascular smooth muscle cell (SMC) response to IGF-I in vivo. PAPP-A transgenic (Tg) and wild-type (WT) mice underwent unilateral carotid ligation, a model of injury-induced SMC hyperplasia and neointimal formation. In both WT and PAPP-A Tg mice, endogenous PAPP-A mRNA expression showed peak elevation 5 days after carotid ligation. However, PAPP-A Tg mice had 70-75% less neointima than WT at 5 and 10 days postligation, with a significant reduction in occlusion of the ligated artery. WT and PAPP-A Tg mice had equivalent increases in medial area and vessel remodeling postligation. There was little change in medial area and no evidence of neointima in the contralateral carotid of WT or PAPP-A Tg mice. Both WT and PAPP-A Tg carotids exhibited signs of dedifferentiation of SMC, which precedes the increase in proliferation and migration that results in neointimal formation. However, the number of proliferating cells in the media and neointima of the ligated PAPP-A Tg artery was reduced by 90% on day 5 postsurgery compared with WT. This decrease was associated with a significant decrease in an in vivo marker of IGF-I bioactivity and reduced IGF-I-stimulated receptor phosphorylation ex vivo. These data suggest differential effects of chronic (transgenic) and transient (endogenous) PAPP-A expression on neointimal formation following vascular injury that may be due in part to the differential impact on IGF-I signaling.