Endothelial Bmp4 is induced during arterial remodeling: Effects on smooth muscle cell migration and proliferation
Endothelial Bmp4 is induced during arterial remodeling: Effects on smooth muscle cell migration and proliferation
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DOI：
10.1016/j.jss.2007.03.077
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发表时间：
2008-03-01
影响因子：
2.2
通讯作者：
Guzman, Raul J.
中科院分区：
文献类型：
--
作者：
Corriere, Matthew A.;Rogers, Chris M.;Guzman, Raul J.
背景骨形态发生蛋白（BMP）是转化生长因子β超家族的成员，在哺乳动物发育中具有多种功能作用。最近提出了BMP 4在成人血管重塑中的作用。我们评估了Bmp 4在体内新生内膜病变发展过程中的表达。使用杂合Bmp 4（lacZ/+）小鼠来评估颈动脉结扎后的体内Bmp 4表达。在颈动脉结扎后1至14天的组织切片中评价β-半乳糖苷酶（β-gal）活性，并与对照颈动脉进行比较。用大鼠主动脉平滑肌细胞系评价重组人BMP 4对平滑肌细胞迁移和增殖的影响。接下来，我们通过使用腺病毒介导的基因转移过表达组成型活性BMP受体（BMPR-IA/Alk-3）来评估BMP 4信号传导的作用。在腺病毒转染的细胞中检测SMC的增殖、迁移和凋亡。结扎颈动脉后1d表达内皮特异性β-gal染色。染色强度在结扎后3d和1周均增加，并在2周时保持稳定，而对照血管中未观察到β-gal染色。通过PECAM-1的阳性染色证实β-半乳糖苷酶的内皮特异性表达。当将人重组BMP 4加入到培养的SMC中时，它抑制迁移，但不影响培养的SMC增殖。用编码活性BMP受体Alk-3的腺病毒感染的SMC表现出剂量依赖性受体表达。ALK-3过表达细胞的增殖和迁移呈剂量依赖性下降，但对凋亡无影响。这些结果表明，在体内颈动脉结扎后，内皮Bmp 4表达上调，此外，激活BMP信号级联导致SMC增殖和迁移减少。这表明，骨形成蛋白可能会抵消在新生内膜增生的发展过程中观察到的丝裂原上调的影响。(c)2008年爱思唯尔公司All rights reserved.
Background. Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-beta superfamily of proteins that have multiple functional roles in mammalian development. A role for BMP4 in adult vascular remodeling has recently been suggested. We evaluated the expression of Bmp4 during neointimal lesion development in vivo.Materials and methods. Heterozygous Bmp4(lacZ/+) mice were used to evaluate in vivo Bmp4 expression after carotid ligation. beta-galactosidase (beta-gal) activity was evaluated in histological sections 1 to 14 d after carotid ligation and this was compared with control carotid arteries. The effects of recombinant human (rh) BMP4 on smooth muscle cell (SMC) migration and proliferation were evaluated using a rat aortic SMC line. We next assessed the effects of BMP4 signaling by over-expressing a constitutively active BMP receptor (BMPR-IA/Alk-3) using adenovirus-mediated gene transfer. SMC proliferation, migration, and apoptosis were evaluated in adenovirus transfected cells.Results. Ligated carotid arteries expressed endothelium-specific beta-gal staining after 1 d. Staining intensity increased at both 3 d and 1 wk after ligation and remained stable at 2 weeks while no beta-gal staining was observed in control vessels. Endothelial-specific expression of beta-galactosidase was confirmed through positive staining for PECAM-1. When human recombinant BMP4 was added to cultured SMCs, it inhibited migration but did not affect cultured SMC proliferation. SMCs infected with adenovirus encoding for the active BMP receptor Alk-3 demonstrated dose-dependent receptor expression. Alk-3 over-expressing cells showed a dose-dependent decrease in proliferation and migration but no effect on apoptosis.Conclusions. These results demonstrate that endothelial Bmp4 expression is upregulated after carotid ligation in vivo, and furthermore, that activating the BMP signaling cascade results in decreased SMC proliferation and migration. This suggests that BMPs may counterbalance the effect of mitogen up-regulation observed during the development of neointimal hyperplasia. (c) 2008 Elsevier Inc. All rights reserved.