Age-related increase of stem marker expression influences vascular smooth muscle cell properties
Age-related increase of stem marker expression influences vascular smooth muscle cell properties
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DOI：
10.1016/j.atherosclerosis.2012.07.016
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发表时间：
2012-09-01
期刊：
影响因子：
5.3
通讯作者：
Orlandi, Augusto
中科院分区：
文献类型：
--
作者：
Ferlosio, Amedeo;Arcuri, Gaetano;Orlandi, Augusto
目的：衰老是血管疾病发展的主要危险因素。随着年龄的增长，血管平滑肌细胞(SMC)的生物学特性发生了变化。干细胞标记物的表达是SMC在发育生长和动脉粥样硬化过程中的特征，但具有干细胞特征的SMC在与年龄相关的动脉重构中的作用尚不清楚。方法和结果：免疫组织化学染色显示，正常青年(17-30岁)大动脉和2月龄大鼠主动脉中膜中罕见的血管生长因子受体-1(Flt-1(+))和c-kit(+)细胞，而CD133(+)细胞缺失。在老年供者(-77岁)的大动脉中，Flt-1(+)和c-kit(+)细胞数量增加，内膜增厚和中膜。双重免疫荧光显示30.6+/-3%的Flt-1(+)内膜细胞共表达α-平滑肌肌动蛋白。免疫组织化学染色、免疫印迹和RT-PCR证实Flt-1和c-kit在20~24月龄大鼠主动脉中膜中的表达增加。在体外，与年轻大鼠相比，老年大鼠主动脉平滑肌细胞增殖和迁移更多，Flt-1、c-kit、NF-kappa B、VCAM-1、IAP-1和MCP-1水平更高，而α-平滑肌肌动蛋白和肌球蛋白水平更低。与年轻的SMC相比，老年的SMC对全反式维甲酸和核因子-kappaB抑制诱导的细胞凋亡也更敏感。结论：Flt-1(+)和c-kit(+)SMC的增多是老年供者大动脉的特征；Flt-1信号的阻断影响了老年SMC的行为，提示具有干性表型的SMC的积聚参与了年龄依赖性的不良动脉重构。(C)2012爱思唯尔爱尔兰有限公司。保留所有权利。
Objective: Aging represents a major risk factor for vascular disease development. With aging, changes of the biological properties of vascular smooth muscle cells (SMCs) are observed. Stem marker expression characterizes SMCs during developmental growth and atherosclerosis, but the contribution of SMCs with stem features to the age-related arterial remodeling remains largely unknown.Methods and results: Immunostaining revealed rare vascular growth factor receptor-1(+) (flt-1(+)) and c-kit(+) cells in tunica media of grossly normal human young (17-30 years old) large arteries and 2-month old rat aorta, whereas CD133(+) cells were absent. In large arteries of human aged donors (64-77 years), flt-1(+) and c-kit(+) cell number increased in the intimal thickening and tunica media. Double immunofluorescence revealed that 30.6 +/- 3% of flt-1(+) intimal cells co-expressed alpha-smooth muscle actin. Immunostaining, blots and RT-PCR documented the increased expression of flt-1 and c-kit in 20-24-month old rat aortic media. In vitro, old rat aortic SMCs proliferated and migrated more with greater flt-1, c-kit, NF-kappa B, VCAM-1, IAP-1 and MCP-1 levels and less alpha-smooth muscle actin and myosin compared to young SMCs. Old SMCs were also more susceptible to all-trans retinoic and NF-kappa B inhibition-induced apoptosis compared to young SMCs. Anti-flt-1 blocking antibody reduced migration and placental growth factor-induced but not serum and PDGF-BB-stimulated proliferation of old SMCs.Conclusions: The increase of flt-1(+) and c-kit(+) SMCs characterizes large arteries of aged donors; the blocking of flt-1 signaling influences the behavior of old SMCs, suggesting that the accumulation of SMCs with a stem phenotype contributes to the age-dependent adverse arterial remodeling. (c) 2012 Elsevier Ireland Ltd. All rights reserved.