Gremlin promotes vascular smooth muscle cell proliferation and migration
Gremlin promotes vascular smooth muscle cell proliferation and migration
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DOI：
10.1016/j.yjmcc.2007.10.021
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发表时间：
2008-02-01
影响因子：
5
通讯作者：
Campos, Alexandre H.
中科院分区：
文献类型：
--
作者：
Maciel, Thiago T.;Melo, Rosilene S.;Campos, Alexandre H.
最近的报道强调了BMP在血管系统中的重要性。我们研究了BNIP拮抗剂gremlin在VSMC中的表达模式和作用。我们检测了成年和胚胎大鼠主动脉VSMC以及大鼠颈动脉中gremlin mRNA的组成性表达。体外分析表明，血管紧张素II，TGF-β 1和PDGF诱导gremlin mRNA表达的显着变化。Gremlin在A7 r5细胞中的稳定过表达阻断了BMP信号传导。BMP诱导的VSMC DNA合成减少被gremlin过表达显著抑制。事实上，gremlin过表达通过包括p27（kip 1）下调在内的机制增加了DNA合成和细胞计数，并加速了VSMC的细胞周期进程。Gremlin还导致了VSMC迁移的显著增加。此外，gremlin基因沉默促进了对细胞增殖和迁移的显著阻断。体内研究显示，球囊损伤的颈动脉新生内膜中gremlin蛋白表达增加。总之，BMP拮抗剂gremlin在正常脉管系统中组成型表达。Gremlin诱导VSMC增殖和迁移，并受生长因子和损伤的显著调节。我们推测gremlin在成人VSMC的病理表型变化的发展中起着重要作用。(c)2007年爱思唯尔公司All rights reserved.
Recent reports highlight the importance of BMP in the vasculature. We investigated the expression pattern and role of the BNIP antagonist gremlin in VSMC. We detected gremlin mRNA constitutive expression in adult and embryonic rat aortic VSMC, and in rat carotids. In vitro analysis demonstrated that angiotensin II, TGF-beta 1 and PDGF induced significant changes in gremlin mRNA expression. Gremlin stable overexpression in A7r5 cells blocked BMP signaling. BMP-mduced reduction in VSMC DNA synthesis was markedly inhibited by gremlin overexpression. In fact, gremlin overexpression increased DNA synthesis and cell counts, and accelerated cell cycle progression of VSMC, through mechanisms that include p27(kip1) down-regulation. Gremlin also led to marked increments in VSMC migration. In addition, gremlin gene silencing promoted a significant blockade on cell proliferation and migration. In vivo studies disclosed increased gremlin protein expression in the neointima of balloon-injured carotid arteries. In summary, the BMP antagonist gremlin is constitutively expressed in the normal vasculature. Gremlin induces VSMC proliferation and migration and is significantly regulated by growth factors and injury. We postulate that gremlin plays a part in the development of pathological phenotypic changes of adult VSMC. (c) 2007 Elsevier Inc. All rights reserved.