MECHANISMS OF ARTERIAL GRAFT HEALING

在这个项目中，我们正在研究血管内膜增厚是如何发生的。 聚四氟乙炔动脉移植物(PTFE)和损伤动脉 在狒狒身上。在过去的一年里，我们坚持假设硝酸根 一氧化氮(NO)是平滑肌细胞(SMC)的主要负性调节因子。 血管的生长，因为高血流抑制了血管内膜 内皮型一氧化氮合酶基因的增厚和诱导 (EcNOS)。我们用药物阻断ecNOS原因的实验 血管收缩，但不会诱导SMC增殖，除非 某种程度的伤害。此外，我们还进行了实验 用抗血小板衍生生长因子受体的抗体(和) (PDGF-R-(和())，以确定PDGF在内膜增厚中的作用。 PDGFR-(阻断抑制损伤或血管内膜增厚 切换血液流动。PDGFR-(阻断不抑制血管内膜 增生，但可能导致细胞死亡。我们目前正在研究 高血流量如何导致内膜退变的问题 并正在测试NO可能是导致 血管内皮细胞凋亡。我们还试图延长我们的工作 到临床应用。我们已经开发了一个外植体系统，并已经 表明外植体中SMC的生长与SMC的生长非常相似 动脉受伤。我们现在希望用外植体系统来定义 人大隐静脉外植体中人血管平滑肌细胞的特性。终极的 目标是在动物研究和结果之间提供联系 人类。资助NIH拨款RR00166、HL30946和HL18645。赫丁，美国， A.W.肝素抑制凝血酶诱导 动脉平滑肌中的丝裂原活化蛋白激酶信号转导 细胞。J.VASC.外科手术27：512-520,1998。首页--期刊主要分类--期刊细介绍--期刊题录与文摘--文摘内容 Levkau，B.，Wang，Y.，Davies，M.G.和Clowes，A.W.Pervadate 抑制细胞内丝裂原激活的蛋白激酶-1 P38MAPK依赖方式。费布斯·莱特。427：271-274,1998道姆，G. Levkau，B.，Chamberlain，N.L.，Wang，Y.和Clowes，A.W.The 丝裂原激活的激酶途径参与钒酸盐的毒性 血管平滑肌细胞。莫莱克。牢房。生物化学。183：97-103， 1998年。小丑、A.W.血管外科和血管基因疗法。J. 心脏。《外科杂志》第39期(增刊1)185-188,1998年。小山，N.，Kinsella， M.G.，鬼魂，T.N.，赫丁，美国和小丑，A.W.硫酸乙酰肝素 蛋白多糖介导了一种有效的抑制细胞迁移的信号 血管平滑肌细胞。中国保监会。结果83：305-313,1998。 首页--期刊主要分类--期刊细介绍--期刊题录与文摘--期刊详细文摘内容 Corson，M.A.，Au，Y.P.T.，Hanson，S.R.和Clowes，A.W.很顺利 内皮型一氧化氮对灵长类动物动脉肌肉生长的调节 氧化物合成酶？J.VASC.外科手术28：514-521,1998。费舍尔，J.W. 戴维斯，M.G.，鬼魂，T.N.和小丑，A.W.凡西嘉是 主要蛋白多糖在血流促进的血管内膜增生中的作用 内皮化的狒狒血管移植物。发行量98(17增刊)i) 228,1998(摘要)。

In this project we are studying how intimal thickening develops in polytetrafluoroethelyne arterial grafts (PTFE) and in injured arteries in baboons. In the last year we pursued the hypothesis that nitric oxide (NO) is a major negative regulator of smooth muscle cell (SMC) growth in blood vessels, because high blood flow suppresses intimal thickening and induces the endothelial nitric oxide synthase gene (ecNOS). Our experiments with agents to block ecNOS cause vasoconstriction but do not induce SMC proliferation unless there is some degree of injury. In addition, we have performed experiments with antibodies to platelet derived growth factor receptor-( and ( (PDGF-R-( and () to define a role for PDGF in intimal thickening. PDGFR-( blockade inhibits intimal thickening induced by injury or a switch in blood flow. PDGFR-( blockade does not inhibit intimal hyperplasia but may cause cell death. We are currently working on the problem of how high blood flow causes regres sion of intimal thickening and are testing the hypothesis that NO may be causing smooth muscle cell apoptosis. We have also tried to extend our work to clinical application. We have developed an explant system and have shown that SMC growth in explants resembles very closely SMC growth in injured artery. We now hope to use the explant system to define the properties of human SMCs in saphenous vein explants. The ultimate goal is to provide a link between animal studies and outcome in humans. FUNDING NIH grants RR00166, HL30946, and HL18645. Hedin, U., Daum, G., and Clowes, A.W. Heparin inhibits thrombin-induced mitogen-activated protein kinase signaling in arterial smooth muscle cells. J. Vasc. Surg. 27:512-520, 1998. Daum, G., Kalmes, A., Levkau, B., Wang, Y., Davies, M.G., and Clowes, A.W. Pervanadate inhibits mitogen-activated protein kinase kinase-1 in a p38MAPK-dependent manner. FEBS Lett. 427:271-274, 1998. Daum, G., Levkau, B., Chamberlain, N.L., Wang, Y., and Clowes, A.W. The mitogen-activated kinase pathway contributes to vanadate toxicity in vascular smooth muscle cells. Molec. Cell. Biochem. 183:97-103, 1998. Clowes, A.W. Vascular surgery and vascular gene therapy. J. Cardiovasc. Surg. 39(Suppl 1) 185-188, 1998. Koyama, N., Kinsella, M.G., Wight, T.N., Hedin, U., and Clowes, A.W. Heparan sulfate proteoglycans mediate a potent inhibitory signal for migration of vascular smooth muscle cells. Circ. Res. 83:305-313, 1998. Mattsson, E.J.R., Geary, R.L., Kraiss, L.W., Vergel, S., Liao, J.K., Corson, M.A., Au, Y.P.T., Hanson, S.R., and Clowes, A.W. Is smooth muscle growth in primate arteries regulated by endothelial nitric oxide synthase? J. Vasc. Surg. 28:514-521, 1998. Fischer, J.W., Davies, M.G., Wight, T.N., and Clowes, A.W. Versican is the predominant proteoglycan in flow accelerated neointimal hyperplasia of endothelialized baboon vascular grafts. Circulation 98 (17 suppl. I) 228, 1998 (abstract).