Adventitial microvessel formation after coronary stenting and the effects of SU11218, a tyrosine kinase inhibitor
Adventitial microvessel formation after coronary stenting and the effects of SU11218, a tyrosine kinase inhibitor
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DOI：
10.1016/j.jacc.2005.08.076
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发表时间：
2006-03-07
影响因子：
24
通讯作者：
Strauss, BH
中科院分区：
文献类型：
--
作者：
Cheema, AN;Hong, T;Strauss, BH
本研究的目的是描述支架植入术后血管外膜微血管（Ad-MV）形成的时间分布，其与动脉壁缺氧的关系，以及酪氨酸激酶抑制剂（TKI） SU11218对Ad-MV和支架内内膜增生（IH）的影响。研究背景：动脉损伤后出现了血管外微血管；然而，这种反应的潜在刺激及其与IH的关系尚不清楚。方法40头猪进行冠状动脉支架植入术，随机分为SU11218组（n = 20）和安慰剂组（n = 20）。通过吡莫硝唑加合物和缺氧诱导因子(HIF)-1 α的表达评估血管壁缺氧情况。采用三维显微计算机断层扫描（3D micro CT）对血管外微血管进行定量分析。血管内超声（IVUS）、三维显微CT和形态测量术测量内膜增生情况。体外观察SU11218对平滑肌细胞（SMC）和内皮细胞（EC）功能的影响，体内观察SU11218对Ad-MV和IH的影响。结果48 h时血管内缺氧明显，并持续4周。与未损伤动脉（16 +/- 2微血管/节段，p < 0.001）相比，血管外微血管在第1周（24 +/- 7微血管/节段）和第4周（23 +/- 7微血管/节段）显著增加（p < 0.001），并与IH相关（r = 0.77, p < 0.001）。TKI SU11218在体外以剂量依赖性的方式抑制血小板衍生生长因子受体- β磷酸化、EC和SMC DNA合成和迁移，并显著抑制Ad-MV (16 +/- 5 vs.安慰剂中的23 7微血管/段，p < 0.001)，并在体内4周时产生约80%的IH降低(0.52 +/- 0.51 mm（2) vs.安慰剂中的2.47 +/- 1.66 mm(2), p < 0.001）。结论动脉支架植入术引起动脉壁缺氧，并伴Ad-MV形成。TKI SU11218抑制Ad-MV形成和IH，是一种有前景的治疗药物，可预防支架内再狭窄。
OBJECTIVES The aim of this study was to delineate the temporal profile of adventitial microvessel (Ad-MV) formation after stenting, its relationship to arterial wall hypoxia, and the effects of a tyrosine kinase inhibitor (TKI), SU11218, on Ad-MV and in-stent intimal hyperplasia (IH).BACKGROUND Adventitial microvessels have been reported after arterial injury; however, the underlying stimulus for this response and its relationship to IH is unknown.METHODS Coronary stenting was performed in 40 pigs randomized to SU11218 (n = 20) or placebo (n = 20). Vessel wall hypoxia was assessed by pimonidazole adducts and hypoxia-inducible factor (HIF)-1 alpha expression. Adventitial microvessels were quantified by three-dimensional microscopic computed tomography (3D micro CT). Intimal hyperplasia was measured by intravascular ultrasound (IVUS), 3D micro CT, and morphometry. The effects of SU11218 were assessed in vitro on smooth muscle cell (SMC) and endothelial cell (EC) functions and in vivo on Ad-MV and IH.RESULTS Hypoxia was evident in the vessel wan at 48 h and persisted for four weeks. Adventitial microvessels increased significantly at one week (24 +/- 7 microvessels/segment) and four weeks (23 +/- 7 microvessels/segment) compared with uninjured arteries (16 +/- 2 microvessels/segment; p < 0.001) and correlated with IH (r = 0.77, p < 0.001). The TKI SU11218 inhibited platelet-derived growth factor receptor-beta phosphorylation, EC and SMC DNA synthesis, and migration in a dose-dependent manner in vitro and significantly inhibited Ad-MV (16 +/- 5 vs. 23 7 microvessels/segment in placebo, p < 0.001) and produced 2 approximately 80% reduction in IH (0.52 +/- 0.51 mm(2) vs. 2.47 +/- 1.66 mm(2) in placebo, p < 0.001) at four weeks in vivo.CONCLUSIONS Arterial stenting causes arterial wall hypoxia followed by Ad-MV formation. The TKI SU11218 inhibits both Ad-MV formation and IH and represents a promising therapeutic agent to prevent in-stent restenosis.