VASCULAR SMOOTH MUSCLE CELL PROLIFERATION

平滑肌细胞（SMC），血液中最丰富的细胞类型 血管壁，主要负责收缩和维护 血管张力。 它们通常在体内具有低复制率; 然而，SMC增殖被认为是发病机制中的关键事件， 动脉粥样硬化和移植相关动脉硬化。 平滑肌细胞增殖也有助于再狭窄的发展， 冠状动脉血管成形术和合成旁路移植物的闭塞。 基于这些原因，我们实验室的长期目标是确定 调节SMC在体内生长的分子机制。 酸性 成纤维细胞生长因子（aFGF）和碱性成纤维细胞生长因子（bFGF） 是FGF家族七个成员中最具特征的成员 结构上相关的多肽。 它们是有效的SMC有丝分裂原， 由血管壁的正常驻留细胞表达。 因此 该提案的前两个具体目标是：1）确定 AFGF或BFGF表达升高的生物学后果， 表征产生高水平这些多肽的SMC系 天然或作为cDNA转染的结果，和2）确定是否 AFGF、BFGF和/或FGF受体基因的表达在细胞周期中被调节。 动脉粥样硬化病变发展和/或在 动脉粥样硬化动脉球囊损伤。 这些实验将 以新西兰白色家兔为模型研究动脉粥样硬化的形成 和血管成形术诱导的再狭窄。 虽然数据已经积累 表明AFGF和BFGF可能在SMC生长中起关键作用 对照，目前尚不清楚是否有任何含有信号肽的 FGF家族的成员也可能是重要的。 第三， 本提案具体目的是确定是int-2还是FGF-5， 在FGF家族的五个含有信号序列的成员中， 多肽，值得考虑作为SMC生长控制的介质 in vivo. 最初的实验将测试这些蛋白质的能力， 以刺激人SMC增殖。 如果它们是促有丝分裂的， 研究检测了int-2和FGF-5基因表达的调节， 体外、体内和体内的血管细胞也将启动。 从本提案中描述的研究计划中获得的结果可能 帮助合理设计具体的治疗方法， SMC增生问题。

Smooth muscle cells (SMCs), the most abundant cell type in the blood vessel wall, are primarily responsible for contraction and maintenance of vascular tone. They generally have a low replication rate in vivo; however, SMC proliferation is regarded as a key event in the pathogenesis of both atherosclerosis and transplantation-associated arteriosclerosis. SMC proliferation also contributes to the development of restenosis after coronary angioplasty and to the occlusion of synthetic bypass grafts. For these reasons, the long-term goal of our laboratory is to identify the molecular mechanisms that regulate SMC growth in vivo. Acidic fibroblast growth factor (aFGF) and basic fibroblast growth factor (bFGF) are the best characterized members of the FGF family of seven structurally related polypeptides. They are potent SMC mitogens and are expressed by the normal resident cells of the vessel wall. Thus, the first two specific aims of this proposal are: 1) to determine the biological consequences of elevated AFGF or BFGF expression by characterizing SMC lines that produce high levels of these polypeptides naturally or as a result of cDNA transfection and 2) to determine whether AFGF, BFGF and/or FGF receptor gene expression is modulated during atherosclerotic lesion development and/or during the response of atherosclerotic arteries to balloon injury. These experiments will utilize the New Zealand white rabbit as a model to study atherogenesis and angioplasty-induced restenosis. Although data has accumulated indicating that AFGF and BFGF may play a critical role in SMC growth control, it is not yet known whether any of the signal peptide-containing members of the FGF family could also be important. Thus, the third specific aim of this proposal is to determine whether int-2 or FGF-5, two of the five signal sequence-containing members of the FGF family of polypeptides, warrant consideration as mediators of SMC growth control in vivo. Initial experiments will assay the ability of these proteins to stimulate human SMC proliferation. If they are mitogenic, additional studies examining the regulation of int-2 and FGF-5 gene expression by vascular cells in vitro and in vivo and in vivo will also be initiated. Results obtained from the research program described in this proposal may aid in the rational design of specific therapeutic approaches to the problem of SMC hyperplasia.