Endothelial repair in stented arteries is accelerated by inhibition of Rho-associated protein kinase.
Endothelial repair in stented arteries is accelerated by inhibition of Rho-associated protein kinase.
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DOI：
10.1093/cvr/cvw210
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发表时间：
2016-12
影响因子：
10.8
通讯作者：
Evans PC
中科院分区：
文献类型：
--
作者：
Hsiao ST;Spencer T;Boldock L;Prosseda SD;Xanthis I;Tovar-Lopez FJ;Van Beusekom HM;Khamis RY;Foin N;Bowden N;Hussain A;Rothman A;Ridger V;Halliday I;Perrault C;Gunn J;Evans PC
支架展开引起内皮细胞（EC）剥脱，这促进了支架内再狭窄和血栓形成。因此，支架动脉中的内皮再生是重要的治疗目标。支架支柱改变局部血流动力学，但血流扰动对EC损伤和修复的影响尚不完全清楚。通过研究支架支柱对血流和EC迁移的影响，我们确定了一种促进支架动脉内皮修复的干预措施。开发了体外和体内模型，以监测血流下的内皮化和支架支柱的影响。使用具有垂直于流动布置的100 μm脊的2D平行板流动室。活细胞成像耦合到计算流体动力学模拟显示，EC迁移的流动方向上游的山脊，但随后积累的双向流动的网站从山脊下游。EC捕获双向流动的机制涉及减少迁移极性与改变肌动蛋白动力学。抑制Rho相关蛋白激酶（ROCK）可通过促进双向流动下的迁移极性而促进脊状表面的内皮化（P < 0.01）。为了更接近地模拟体内情况，我们在含有Coroflex Blue支架（65 μm支柱）的聚二甲基硅氧烷管的内表面上培养EC并监测迁移。ROCK抑制剂显著增加了流动下支架下游的EC积聚（P < 0.05）。我们使用猪EC剥脱和支架置入模型研究了ROCK抑制对体内再内皮化的影响。共聚焦显微镜观察显示，法舒地尔（30 mg/d，通过渗透压微泵）抑制ROCK可显著增加支架后颈动脉的再内皮化（P < 0.05）。支架支柱通过产生局部双向流动来阻滞迁移的EC，从而延迟内皮修复。ROCK抑制剂通过增强EC极性和通过双向流动区域的迁移来加速支架植入动脉的内皮修复。
Stent deployment causes endothelial cells (EC) denudation, which promotes in-stent restenosis and thrombosis. Thus endothelial regrowth in stented arteries is an important therapeutic goal. Stent struts modify local hemodynamics, however the effects of flow perturbation on EC injury and repair are incompletely understood. By studying the effects of stent struts on flow and EC migration, we identified an intervention that promotes endothelial repair in stented arteries. In vitro and in vivo models were developed to monitor endothelialization under flow and the influence of stent struts. A 2D parallel-plate flow chamber with 100 μm ridges arranged perpendicular to the flow was used. Live cell imaging coupled to computational fluid dynamic simulations revealed that EC migrate in the direction of flow upstream from the ridges but subsequently accumulate downstream from ridges at sites of bidirectional flow. The mechanism of EC trapping by bidirectional flow involved reduced migratory polarity associated with altered actin dynamics. Inhibition of Rho-associated protein kinase (ROCK) enhanced endothelialization of ridged surfaces by promoting migratory polarity under bidirectional flow (P < 0.01). To more closely mimic the in vivo situation, we cultured EC on the inner surface of polydimethylsiloxane tubing containing Coroflex Blue stents (65 μm struts) and monitored migration. ROCK inhibition significantly enhanced EC accumulation downstream from struts under flow (P < 0.05). We investigated the effects of ROCK inhibition on re-endothelialization in vivo using a porcine model of EC denudation and stent placement. En face staining and confocal microscopy revealed that inhibition of ROCK using fasudil (30 mg/day via osmotic minipump) significantly increased re-endothelialization of stented carotid arteries (P < 0.05). Stent struts delay endothelial repair by generating localized bidirectional flow which traps migrating EC. ROCK inhibitors accelerate endothelial repair of stented arteries by enhancing EC polarity and migration through regions of bidirectional flow.
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影响因子：
4.8
作者：
Bryan, Brad A.;Dennstedt, Emily;D'Amore, Patricia A.
通讯作者：
D'Amore, Patricia A.
DOI：
10.1152/ajpheart.01107.2004
发表时间：
2005-05-01
影响因子：
4.8
作者：
LaDisa, JF;Olson, LE;Pagel, PS
通讯作者：
Pagel, PS
影响因子：
158.5
作者：
Ellis, Stephen G.;Kereiakes, Dean J.;Stone, Gregg W.
通讯作者：
Stone, Gregg W.
影响因子：
37.8
作者：
Finn, Aloke V.;Joner, Michael;Virmani, Renu
通讯作者：
Virmani, Renu
DOI：
10.1161/01.atv.0000105053.46994.5b
发表时间：
2004-01-01
影响因子：
8.7
作者：
Matsumoto, Y;Uwatoku, T;Shimokawa, H
通讯作者：
Shimokawa, H