Regulation of vascular smooth muscle cell migration and proliferation in vitro and in injured rat arteries by a synthetic matrix metalloproteinase inhibitor
Regulation of vascular smooth muscle cell migration and proliferation in vitro and in injured rat arteries by a synthetic matrix metalloproteinase inhibitor
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DOI：
10.1161/01.atv.16.1.28
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发表时间：
1996-01-01
影响因子：
8.7
通讯作者：
Clowes, AW
中科院分区：
文献类型：
--
作者：
Zempo, N;Koyama, N;Clowes, AW
平滑肌细胞（SMC）迁移和增殖以及细胞外基质重塑是动脉对损伤、血管发育和动脉粥样硬化形成的反应的重要方面。基质金属蛋白酶（MMP）表达与动脉损伤后SMC增殖和迁移有关。为了评估MMP在SMC增殖和迁移以及内膜增厚中的作用，我们测量了合成MMP抑制剂BB 94（巴马司他）对体外SMC的DNA合成和迁移以及球囊损伤大鼠颈动脉后新生内膜形成的影响。BB 94剂量依赖性地抑制由血小板衍生生长因子（PDGF）-BB诱导的SMC迁移通过涂覆有厚基底膜基质（Matrigel）层的滤器，但对SMC迁移通过轻度涂覆的滤器没有显示出任何抑制作用。在浓度高达1 μ mol/L时，BB 94不改变PDGF-AA或PDGF-BB诱导的DNA合成。用30 mg BB 94治疗。kg（-1）。d（-1）IP 7或14天可减少大鼠颈动脉球囊损伤后内膜SMC核总数，抑制内膜增厚。SMC增殖（5-溴-2 '-脱氧尿苷标记）在第2天在中膜中减少，而在第7天而不是第14天在内膜中增加。这些结果表明，BB 94通过减少SMC迁移和增殖抑制动脉损伤后的内膜增厚，并支持MMPs在调节损伤动脉内膜增厚中起重要作用的结论。
Smooth muscle cell (SMC) migration and proliferation and extracellular matrix remodeling are essential aspects of the arterial response to injury, vessel development, and atherogenesis. Matrix metalloproteinase (MMP) expression is associated with SMC proliferation and migration after arterial injury. To assess the role of MMPs in SMC proliferation and migration and intimal thickening, we measured the effect of the synthetic MMP inhibitor BB94 (Batimastat) on DNA synthesis and migration of SMCs in vitro as well as the formation of a neointima after balloon injury to the rat carotid artery. BB94 dose-dependently inhibited SMC migration induced by platelet-derived growth factor (PDGF)-BB through a filter coated with a thick basement membrane matrix (Matrigel) layer but did not show any inhibitory effect on SMC migration through a lightly coated filter. At concentrations up to 1 mu mol/L, BB94 did not alter DNA synthesis induced by PDGF-AA or PDGF-BB. Treatment with 30 mg BB94 . kg(-1) . d(-1) IP for 7 or 14 days after balloon injury to the rat carotid artery decreased the total number of intimal SMC nuclei and suppressed intimal thickening. SMC proliferation (5-bromo-2'-deoxyuridine labeling) was decreased in the media at 2 days, whereas it was increased in the intima at 7 but not 14 days. These results suggest that BB94 inhibits intimal thickening after arterial injury by decreasing SMC migration and proliferation and support the conclusion that MMPs play a significant role in regulating intimal thickening in injured arteries.