MECHANISMS OF ARTERIAL GRAFT HEALING

在这个项目中，我们正在研究如何内膜增厚的发展， 聚四氟乙烯动脉移植物（PTFE）和损伤动脉 在狒狒身上。 去年我们继续研究一个假设 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，因为高血流抑制了内膜 增厚并诱导内皮型一氧化氮合酶基因 （ecNOS）。 我们的实验用药物阻断ecNOS， 血管收缩，但不诱导SMC增殖，除非有 一定程度的伤害。 此外，我们还进行了实验， 用抗血小板衍生生长因子受体抗体-（和（ （PDGF-R-（和（））定义PDGF在内膜增厚中的作用。 PDGFR-（阻断可抑制损伤或炎症诱导的内膜增厚 血液流动的转换。 PDGFR-（阻断不抑制内膜 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锡永的问题 并正在测试一氧化氮可能导致 平滑肌细胞凋亡。 我们还努力扩大我们的工作 临床应用。 我们开发了一种外植体系统， 表明外植体中的SMC生长非常接近于 受伤的动脉 我们现在希望使用外植体系统来定义 隐静脉外植体中人SMC的特性。 最终 目的是提供动物研究和结果之间的联系， 人类 资助NIH赠款RR 00166、HL 30946和HL 18645。 赫丁，美国， Daum，G.，Clowes，A.W.肝素抑制凝血酶诱导的 动脉平滑肌中的丝裂原活化蛋白激酶信号 细胞 J. Vasc. 27：512-520，1998。 Daum，G.，Kalmes，A.， Levkau，B.，王玉，Davies，M.G.，Clowes，A.W.过钒 抑制促分裂原活化蛋白激酶激酶-1， p38 MAPK依赖性表达。 FEBS Lett. 427：271-274，1998. Daum，G.， Levkau，B.，张伯伦，北卡罗来纳州，王玉，Clowes，A.W.的 丝裂原活化激酶途径有助于钒酸盐毒性， 血管平滑肌细胞 Molec. Cell. 183：97-103， 1998. Clowes，A.W.血管外科与血管基因治疗。 J. Cardiovasc. Surg.39（增刊1）185-188，1998。 Koyama，N.，金塞拉 我的天，怀特，T.N.，赫丁，美国，Clowes，A.W.硫酸乙酰肝素 蛋白聚糖介导了一种有效的抑制信号， 血管平滑肌细胞 Circ. Res. 83：305-313，1998. 马特松，E.J.R.，Geary，R.L.，Kraiss，L.W.，Vergel，S.，Liao，J.K.， 科森，硕士，Au，Y.P.T.，Hanson，S.R.，Clowes，A.W.是光滑 内皮型一氧化氮调节灵长类动物动脉肌肉生长 氧化合酶？ J. Vasc. 28：514-521，1998。 Fischer，J.W.， Davies，M.G.，怀特，T.N.，Clowes，A.W. Versican是 在血流加速的新生内膜增生中占优势的蛋白多糖 内皮化狒狒血管移植物。 循环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).