Tronc F, Mallat Z, Lehoux S, Wassef M, Esposito B, Tedgui A
Institut National de la Santé et de la Recherche Médicale (INSERM) U541, Paris, France.
Arterioscler Thromb Vasc Biol. 2000 Dec;20(12):E120-6. doi: 10.1161/01.atv.20.12.e120.
Tears in the internal elastic lamina (IEL) can be observed after chronic increases in arterial blood flow, suggesting a potential role for matrix metalloproteinases (MMPs) in flow-induced vascular remodeling. We undertook to study this phenomenon by constructing an arteriovenous fistula (AVF) between the left common carotid artery (CCA) and the external jugular vein in rabbits. The diameter of the flow-loaded left CCA increased by 13.6+/-1.8% by day 3 after construction of the AVF compared with the right CCA (n=4, P:<0.01) and by 40.7+/-7.5% by day-15 (n=10, P:<0.0001). Increased CCA diameter also coincided with IEL fragmentation. Three days after construction of the AVF, gelatin zymography of protein extracts from left CCAs of untreated rabbits showed a significant increase in the 62-kDa (active MMP-2) activity and the appearance of a lytic band at 92 kDa (pro-MMP-9). In further experiments, MMP activity was inhibited by treatment with doxycycline (DOX) or BB-94, a specific MMP inhibitor. The increase in the 62-kDa gelatinolytic band was abolished in DOX- and BB-94-treated rabbits. The 92-kDa gelatinolytic band was also reduced in DOX-treated animals. Furthermore, both increased left CCA diameter and IEL fragmentation were abolished in DOX- and BB-94-treated rabbits. To evaluate whether nitric oxide was involved in blood flow-induced MMP activation, the rabbits were treated with N:(G)-nitro-L-arginine methyl ester to inhibit nitric oxide synthesis. MMP activities were significantly decreased in the left CCAs of N:(G)-nitro-L-arginine methyl ester-treated animals. Hence, blood flow-induced MMP activation is critical in flow-induced vascular enlargement and IEL fragmentation, and blood flow-induced nitric oxide participates in MMP activation.
在动脉血流长期增加后，可观察到内弹性膜（IEL）撕裂，提示基质金属蛋白酶（MMPs）在血流诱导的血管重塑中可能发挥作用。我们通过在兔左颈总动脉（CCA）和颈外静脉之间构建动静脉瘘（AVF）来研究这一现象。与右侧CCA相比，构建AVF后第3天，血流负荷增加的左CCA直径增加了13.6±1.8%（n = 4，P<0.01），第15天时增加了40.7±7.5%（n = 10，P<0.0001）。CCA直径增加也与IEL断裂同时出现。构建AVF后3天，未处理兔左CCA蛋白提取物的明胶酶谱显示62 kDa（活性MMP-2）活性显著增加，并且在92 kDa处出现裂解带（前MMP-9）。在进一步的实验中，通过用强力霉素（DOX）或特异性MMP抑制剂BB-94处理来抑制MMP活性。在DOX和BB-94处理的兔中，62 kDa明胶酶解带的增加被消除。在DOX处理的动物中，92 kDa明胶酶解带也减少。此外，在DOX和BB-94处理的兔中，左CCA直径增加和IEL断裂均被消除。为了评估一氧化氮是否参与血流诱导的MMP激活，用N(G)-硝基-L-精氨酸甲酯处理兔以抑制一氧化氮合成。在N(G)-硝基-L-精氨酸甲酯处理动物的左CCA中，MMP活性显著降低。因此，血流诱导的MMP激活在血流诱导的血管扩张和IEL断裂中起关键作用，并且血流诱导的一氧化氮参与MMP激活。
