SDF-1α induction in mature smooth muscle cells by inactivation of PTEN is a critical mediator of exacerbated injury-induced neointima formation.
SDF-1α induction in mature smooth muscle cells by inactivation of PTEN is a critical mediator of exacerbated injury-induced neointima formation.
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DOI：
10.1161/atvbaha.111.223701
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发表时间：
2011-06
期刊：
影响因子：
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通讯作者：
Weiser-Evans MC
中科院分区：
文献类型：
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作者：
Nemenoff RA;Horita H;Ostriker AC;Furgeson SB;Simpson PA;VanPutten V;Crossno J;Offermanns S;Weiser-Evans MC
在平滑肌细胞中选择性地失活PTEN启动多个下游事件，驱动新生内膜的形成，包括平滑肌细胞细胞因子/趋化因子的产生，特别是SDF-1α。我们研究了sdf-1α对原代培养的平滑肌细胞和骨髓源性细胞的作用，以及在介导新生内膜形成中的作用。可诱导的、SMC特异的PTEN基因敲除小鼠(PTEN Iko)被培育成Flosed-Stop rosa26-βGal小鼠，以命运图显示成熟的SMC对损伤的反应；小鼠接受野生型绿色荧光蛋白标记的骨髓以跟踪招募。线源性股动脉损伤后，β-Gal(+)SMC在血管内膜和外膜大量聚集。与野生型相比，PTEN Iko小鼠表现出大量的新生内膜形成，复制的内膜和中层βGal(+)SMC增加，损伤后骨髓细胞的血管募集增加。抑制sdf-1α可阻断这些事件，并逆转在PTEN Iko小鼠中观察到的增强的新生内膜形成。大多数招募的GFP(+)细胞巨噬细胞标记阳性，但SMC标记不阳性。SMC-巨噬细胞相互作用导致持续的SMC炎症表型，这种表型依赖于SMC PTEN和SDF-1α的表达。驻留的SMC通过贡献大部分新生内膜细胞、调节炎性细胞的募集和促进外膜重塑，在新生内膜形成中发挥多方面的作用。SMC PTEN-SDF-1α轴是这些事件的关键调节因子。
PTEN inactivation selectively in smooth muscle cells (SMC) initiates multiple downstream events driving neointima formation, including SMC cytokine/chemokine production, in particular SDF-1α. We investigated the effects of SDF-1α on resident SMC and bone marrow-derived cells and in mediating neointima formation. Inducible, SMC-specific PTEN knockout mice (PTEN iKO) were bred to floxed-stop ROSA26-βGal mice to fate-map mature SMC in response to injury; mice received wild-type GFP-labeled bone marrow to track recruitment. Following wire-induced femoral artery injury, βGal(+) SMC accumulate in the intima and adventitia. Compared to wild-type, PTEN iKO mice exhibit massive neointima formation, increased replicating intimal and medial βGal(+)SMC, and enhanced vascular recruitment of bone marrow cells following injury. Inhibiting SDF-1α blocks these events and reverses enhanced neointima formation observed in PTEN iKO mice. Most recruited GFP(+) cells stain positive for macrophage markers, but not SMC markers. SMC-macrophage interactions result in a persistent SMC inflammatory phenotype that is dependent on SMC PTEN and SDF-1α expression. Resident SMC play a multifaceted role in neointima formation by contributing the majority of neointimal cells, regulating recruitment of inflammatory cells, and contributing to adventitial remodeling. The SMC PTEN-SDF-1α axis is a critical regulator of these events.