经皮腔内血管成形术后再狭窄与血管内皮细胞的关系(2)
作者：佚名； 更新时间：2014-12-13
的关注，肾素-血管紧张素-醛固酮系统活性增加可促进平滑肌细胞增生，利用血管紧张素转化酶(AE)抑制剂可减轻内膜增厚。肾上腺皮质激素可抑制平滑肌细胞增生，但临床使用效果并不理想。雌激素对内皮修复有促进作用， White及Krasinski等［23，24］的动物实验均发现雌激素能促进动脉损伤区重内皮化和内皮细胞功能的恢复，血管内皮细胞上发现有雌激素受体的表达，这表明雌激素直接作用于内皮细胞。
NO在再狭窄中的作用是近年来的一个重要进展，NO被认为是维持血管张力的因素之一，主要通过其内皮依赖性扩血管作用，在血管损伤的早期NO对血小板聚集和白细胞的黏附有抑制作用，另外NO还能抑制平滑肌细胞的增生，Guo等［25］用NO供体（CAS-1609）对大鼠进行实验，发现CAS-1609对大鼠主动脉内皮细胞修复有浓度依赖性促进作用，而对PDGF诱发的平滑肌增生有抑制作用，减轻了内膜的增厚。利用NO供体进行一些临床试用也取得了一定的疗效。
蛋白激酶C （PKC）是广泛存在于细胞内的信号传递物质，是内皮细胞增殖所必需的,用12-豆蔻酸-13-乙酸佛波酯直接活化内皮细胞PKC，发现内皮细胞黏附、伸展及移行能力均增强，而用PKC抑制剂则降低了内皮细胞的再生能力，可见PKC激活剂可作为促进重内皮化的一种方法。
六、金属内支架和血管内皮化
金属内支架的应用大大减低了PTA术后的急性动脉闭塞，其形态稳定性限制了血管的回缩，从而防止了不利的血管重构，但金属内支架本身具致凝性，置入血管后需长期抗凝治疗，而且内支架置入并未彻底解决再狭窄的问题，目前认为PTA术后再狭窄是内膜增生和血管重构双重作用的结果，而内支架置入后再狭窄则主要由内膜增生引起［26］。为阻止内膜增厚，许多学者用带有涤纶被膜的内支紲进行实验研究和临床探索，但一直没有肯定的结果，Schurmann等［27］的实验研究发现，与普通支架相比，被膜式支架引起了更严重的内膜增生和炎症反应；Maynar等［28］的一组股动脉临床资料也表明被膜式支架的通畅率并不理想。支架置入部位的早期内皮化可能预防血栓形成和再狭窄。加速支架内皮化的方法目前主要有两种,一是支架置入后局部灌注药物或导入基因,常用的是VEGF；另一方法是支架置入前在体外先种上内皮细胞［29-31］，可选用转基因内皮细胞进行种植［30，31］，此法最大的障碍是支架置入过程中内皮细胞的丢失［30，31］，但支架金属丝侧面往往有内皮细胞残留，这些细胞可重新增殖并覆盖支架［15,31］。
参考文献
1 Friedman RJ, Stemerman MB, Wenz B, et al. The effect of trombocytopenia on experimental arteriosclerotic lesion formation in rabbits: smooth muscle cell proliferation and re-endothelialization. J Clin Invest, 1977， 60:1191-1201.
2 McNamara CA, Sarembock IJ, Gimple LW, et al. Thrombin stimulates proliferation of cultured rat aortic smooth muscle cells by a proteolytically activated receptor. J Clin Invest, 1993， 91:94-98.
3 Thompson MM, Budd JS, Eady SL, et al. Platelet deposition after angioplasty is abolished by restoration of the endothelial cell monolayer. J Vasc Surg, 1994， 19:478-486.
4 Bauters C, de Groote P, Adamantidis M, et al. Proto-oncogene expression in rabbit aorta after wall injury: first marker of the cellular process leading to restenosis after angioplasty? Eur Heart J, 1992， 13:556-559.
5 Casscells AW. Migration of smooth muscle and endothelial cells: critical events in restenosis. Circulation, 1992， 86:723-729.
6 Schwartz RS, Holmes DR Jr, Topol EJ. The restenosis paradigm revisited: an alternative proposal for cellular mechanisms. J Am Coll Cardiol, 1992， 20:1284-1293.
7 Haudenschild CC, Schwartz SM. Endothelial regeneration II： restitution of endothelial continuity. Lab Invest, 1979， 41:407-418.
8 Asahara T, Bauters C, Pastore C, et al. Local delivery of vascular endothelial growth factor accelerates reendothelialization and attenuates intimal hyperplasia in balloon-injured rat carotid artery. Circulation, 1995，91:2793-2801.
9 Oberhoff M, Novak S, Herdeg C, et al. Local and systemic delivery of low molecular weight heparin stimulates the reendothelialization after balloon angioplasty. Cardiovasc Res, 1998, 38:751-762.
10 Peiro C, Redondo J, Rodriguez-Martinez MA, et al. Influence of endothelium on cultured vascular smooth muscle cell proliferation. Hypertension, 1995，25:748-751.
11 Galis ZS, Muszynski M, Sukhova GK, et al. Cytokine-stimulated human vascular smooth muscle cells synthesize a complement of enzymes required for extracellular matrix digestion. Circ Res, 1994，75:181-189.
12 Woessner JF. Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J, 1991，5:2145-2154.
13 Libby P, Tanaka H. The molecular bases of restenosis. Prog Cardiovasc Dis, 1997，40:97-106.
14 Rogers C, Parikh S, Seifert P, et al. Endogenous cell seeding: remnant endothelium after stenting enhances vascular repair. Circulation, 1996，94:2909-2914.
15 Weidinger FF, McLenachan JM, Cybulski MI, et al. Persistent dysfunction of regenerated endothelium after balloon angioplasty of rabbit iliac artery. Circulation, 1990，81:1667-1679.
16 Saroyan RM, Roberts MP, Light JT Jr, et al. Differential recovery of prostacyclin and endothelium-derived relaxing factor after vascular injury. Am J Physiol, 1992，262:H1449-H1457.
17 Wilson JM, Birinyi LK, Salomon RN, et al. Implantation of vascular grafts lined with genetically modified endothelial cells. Science, 1989，244:1344-1346.
18 Conte MS, Birinyi LK, Miyata T, et al. Efficient repopulation of denuded rabbit arteries with autologous genetically modified endothelial cells. Circulation, 1994，89:2161-2169.
19 Consigny PM, Vitali NJ. Resistance of freshly adherent endothelial cells to detachment by shear stress is matrix and time dependent. J Vasc Interv Radiol, 1998，9:479-485.
20 Dunn PF, Newman KD, Jones M, et al. Seeding of vascular grafts with genetically modified endothelial cells: secretion of recombinant TPA results in decreased seeded cell retention in vitro and in vivo. Circulation, 1996，93:1439-1446.
21 Madri JA, Reidy MA, Kocher O, et al. Endothelial cell behavior after denudation injury is modulated by transforming growth factor-beta1 and fibronectin. Lab Invest, 1989，60:755-765.
22 Asahara T, Chen D, Tsurumi Y, et al. Accelerated restitution of endothelial integrity and endothelium-dependent function after phVEGF165 gene transfer. Circulation, 1996，94:3291-3302.
23 White CR, Shelton J, Chen SJ, et al. Estrogen restores endothelial cell function in an experimental model of vascular injury. Circulation, 1997，96:1624-1630.
24 Krasinski K, Spyridopoulos I, Asahara T, et al. Estradiol accelerates functional endothelial recovery after arterial injury. Circulation, 1997，95:1768-1772.
25 Guo JP, Panday MM, Consigny PM, et al. Mechanisms of vascular preservation by a novel NO donor following rat carotid artery intimal injury. Am J Physiol, 1995， 269:H1122-H1131.
26 Di Mario C, Gil R,
NO在再狭窄中的作用是近年来的一个重要进展，NO被认为是维持血管张力的因素之一，主要通过其内皮依赖性扩血管作用，在血管损伤的早期NO对血小板聚集和白细胞的黏附有抑制作用，另外NO还能抑制平滑肌细胞的增生，Guo等［25］用NO供体（CAS-1609）对大鼠进行实验，发现CAS-1609对大鼠主动脉内皮细胞修复有浓度依赖性促进作用，而对PDGF诱发的平滑肌增生有抑制作用，减轻了内膜的增厚。利用NO供体进行一些临床试用也取得了一定的疗效。
蛋白激酶C （PKC）是广泛存在于细胞内的信号传递物质，是内皮细胞增殖所必需的,用12-豆蔻酸-13-乙酸佛波酯直接活化内皮细胞PKC，发现内皮细胞黏附、伸展及移行能力均增强，而用PKC抑制剂则降低了内皮细胞的再生能力，可见PKC激活剂可作为促进重内皮化的一种方法。
六、金属内支架和血管内皮化
金属内支架的应用大大减低了PTA术后的急性动脉闭塞，其形态稳定性限制了血管的回缩，从而防止了不利的血管重构，但金属内支架本身具致凝性，置入血管后需长期抗凝治疗，而且内支架置入并未彻底解决再狭窄的问题，目前认为PTA术后再狭窄是内膜增生和血管重构双重作用的结果，而内支架置入后再狭窄则主要由内膜增生引起［26］。为阻止内膜增厚，许多学者用带有涤纶被膜的内支紲进行实验研究和临床探索，但一直没有肯定的结果，Schurmann等［27］的实验研究发现，与普通支架相比，被膜式支架引起了更严重的内膜增生和炎症反应；Maynar等［28］的一组股动脉临床资料也表明被膜式支架的通畅率并不理想。支架置入部位的早期内皮化可能预防血栓形成和再狭窄。加速支架内皮化的方法目前主要有两种,一是支架置入后局部灌注药物或导入基因,常用的是VEGF；另一方法是支架置入前在体外先种上内皮细胞［29-31］，可选用转基因内皮细胞进行种植［30，31］，此法最大的障碍是支架置入过程中内皮细胞的丢失［30，31］，但支架金属丝侧面往往有内皮细胞残留，这些细胞可重新增殖并覆盖支架［15,31］。
参考文献
1 Friedman RJ, Stemerman MB, Wenz B, et al. The effect of trombocytopenia on experimental arteriosclerotic lesion formation in rabbits: smooth muscle cell proliferation and re-endothelialization. J Clin Invest, 1977， 60:1191-1201.
2 McNamara CA, Sarembock IJ, Gimple LW, et al. Thrombin stimulates proliferation of cultured rat aortic smooth muscle cells by a proteolytically activated receptor. J Clin Invest, 1993， 91:94-98.
3 Thompson MM, Budd JS, Eady SL, et al. Platelet deposition after angioplasty is abolished by restoration of the endothelial cell monolayer. J Vasc Surg, 1994， 19:478-486.
4 Bauters C, de Groote P, Adamantidis M, et al. Proto-oncogene expression in rabbit aorta after wall injury: first marker of the cellular process leading to restenosis after angioplasty? Eur Heart J, 1992， 13:556-559.
5 Casscells AW. Migration of smooth muscle and endothelial cells: critical events in restenosis. Circulation, 1992， 86:723-729.
6 Schwartz RS, Holmes DR Jr, Topol EJ. The restenosis paradigm revisited: an alternative proposal for cellular mechanisms. J Am Coll Cardiol, 1992， 20:1284-1293.
7 Haudenschild CC, Schwartz SM. Endothelial regeneration II： restitution of endothelial continuity. Lab Invest, 1979， 41:407-418.
8 Asahara T, Bauters C, Pastore C, et al. Local delivery of vascular endothelial growth factor accelerates reendothelialization and attenuates intimal hyperplasia in balloon-injured rat carotid artery. Circulation, 1995，91:2793-2801.
9 Oberhoff M, Novak S, Herdeg C, et al. Local and systemic delivery of low molecular weight heparin stimulates the reendothelialization after balloon angioplasty. Cardiovasc Res, 1998, 38:751-762.
10 Peiro C, Redondo J, Rodriguez-Martinez MA, et al. Influence of endothelium on cultured vascular smooth muscle cell proliferation. Hypertension, 1995，25:748-751.
11 Galis ZS, Muszynski M, Sukhova GK, et al. Cytokine-stimulated human vascular smooth muscle cells synthesize a complement of enzymes required for extracellular matrix digestion. Circ Res, 1994，75:181-189.
12 Woessner JF. Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J, 1991，5:2145-2154.
13 Libby P, Tanaka H. The molecular bases of restenosis. Prog Cardiovasc Dis, 1997，40:97-106.
14 Rogers C, Parikh S, Seifert P, et al. Endogenous cell seeding: remnant endothelium after stenting enhances vascular repair. Circulation, 1996，94:2909-2914.
15 Weidinger FF, McLenachan JM, Cybulski MI, et al. Persistent dysfunction of regenerated endothelium after balloon angioplasty of rabbit iliac artery. Circulation, 1990，81:1667-1679.
16 Saroyan RM, Roberts MP, Light JT Jr, et al. Differential recovery of prostacyclin and endothelium-derived relaxing factor after vascular injury. Am J Physiol, 1992，262:H1449-H1457.
17 Wilson JM, Birinyi LK, Salomon RN, et al. Implantation of vascular grafts lined with genetically modified endothelial cells. Science, 1989，244:1344-1346.
18 Conte MS, Birinyi LK, Miyata T, et al. Efficient repopulation of denuded rabbit arteries with autologous genetically modified endothelial cells. Circulation, 1994，89:2161-2169.
19 Consigny PM, Vitali NJ. Resistance of freshly adherent endothelial cells to detachment by shear stress is matrix and time dependent. J Vasc Interv Radiol, 1998，9:479-485.
20 Dunn PF, Newman KD, Jones M, et al. Seeding of vascular grafts with genetically modified endothelial cells: secretion of recombinant TPA results in decreased seeded cell retention in vitro and in vivo. Circulation, 1996，93:1439-1446.
21 Madri JA, Reidy MA, Kocher O, et al. Endothelial cell behavior after denudation injury is modulated by transforming growth factor-beta1 and fibronectin. Lab Invest, 1989，60:755-765.
22 Asahara T, Chen D, Tsurumi Y, et al. Accelerated restitution of endothelial integrity and endothelium-dependent function after phVEGF165 gene transfer. Circulation, 1996，94:3291-3302.
23 White CR, Shelton J, Chen SJ, et al. Estrogen restores endothelial cell function in an experimental model of vascular injury. Circulation, 1997，96:1624-1630.
24 Krasinski K, Spyridopoulos I, Asahara T, et al. Estradiol accelerates functional endothelial recovery after arterial injury. Circulation, 1997，95:1768-1772.
25 Guo JP, Panday MM, Consigny PM, et al. Mechanisms of vascular preservation by a novel NO donor following rat carotid artery intimal injury. Am J Physiol, 1995， 269:H1122-H1131.
26 Di Mario C, Gil R,
