VASCULAR SMOOTH MUSCLE CELL PROLIFERATION

平滑肌细胞(SMCs)，血液中含量最丰富的细胞类型 血管壁，主要负责收缩和维护 血管紧张度。它们在体内的复制率通常很低； 然而，SMC的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。 SMC增殖也是术后再狭窄发生的原因之一 冠状动脉成形术和人造血管搭桥术的闭塞。 出于这些原因，我们实验室的长期目标是确定 体内调控SMC生长的分子机制。酸性的 成纤维细胞生长因子和碱性成纤维细胞生长因子 是成纤维细胞生长因子家族七口之家中最具个性的成员 结构上相关的多肽。它们是强有力的SMC有丝分裂原，并且 由血管壁的正常驻留细胞表达。因此， 本提案的前两个具体目标是：1)确定 碱性成纤维细胞生长因子或碱性成纤维细胞生长因子表达升高的生物学后果 高水平产生这些多肽的SMC株系的特征 自然或由于cDNA3)转染法和2)确定 成纤维细胞生长因子、碱性成纤维细胞生长因子和/或成纤维细胞生长因子受体基因在 动脉粥样硬化病变的发展和/或在 动脉粥样硬化到球囊损伤。这些实验将 以新西兰大白兔为模型研究动脉粥样硬化形成 和血管成形术引起的再狭窄。尽管数据积累了 提示AFGF和bFGF在SMC生长中可能起重要作用 对照，目前还不知道是否有任何含有信号肽的 成纤维细胞生长因子家族的成员也可能很重要。因此，第三个 这项提议的具体目的是确定INT-2或FGF5，2 在含有信号序列的成纤维细胞生长因子家族的五个成员中 多肽，值得考虑作为SMC生长控制的介体 在活体内。初步实验将分析这些蛋白质的能力。 刺激人SMC增殖。如果它们是有丝分裂的，则另外 对INT-2和FGF5基因表达调控的研究 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 帮助合理设计特定的治疗方法，以治疗 SMC增生的问题。

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.