Intracellular signals and smooth muscle cell migration

血管损伤后，内侧平滑肌细胞（SMC）向内膜内迁移是动脉粥样硬化和再收缩病变发生过程中重构的主要组成部分。生长因子如PDGF和神经营养因子，分别激活PDGF和trk受体酪氨酸激酶，是血管SMC的有效趋化剂。细胞迁移受到高度调控，首先需要细胞脱离细胞外基质，其次是细胞骨架的重组，最后是基质金属蛋白酶的释放，以降解基膜，并允许SMC从介质进入内膜。协调细胞脱离、细胞骨架重组和MMP释放等复杂过程的信号机制尚不明确。本研究的总体目标是分析神经营养因子和PDGF对SMC迁移的下游调控途径，从而确定这两种不同受体酪氨酸激酶是否利用细胞或互补信号机制诱导定向细胞迁移。具体来说，我们计划：1 .确定由生长因子和粘附分子激活的信号通路，这些信号通路在迁移刺激下启动细胞脱离、细胞骨架重组和局灶粘附的转换。2。确定金属蛋白酶在生长因子启动SMC迁移中的作用。3。在明确的血管损伤模型中，直接评估神经营养因子BDNF在病变发展中的作用。在长期高脂饮食和急性颈动脉结扎血流依赖性血管损伤模型中，研究缺乏BDNF或BDNF受体trk B的载脂蛋白E（-/-）小鼠的病变发展。这些研究将使我们能够测试受损的BDNF:trk B信号是否会减少内膜的形成。这些研究涉及与Roy Silverstein博士（项目III）、Kathy Hajjar博士（项目II）和David Hajjar博士（项目VI）的关键互动。

Migration of medial smooth muscle cells (SMC) into the intima in response to vascular injury is a major component of the remodeling which occurs in the development of atherosclerotic and restonotic lesions. Growth factors such as PDGF and the neurotrophins, which activate the PDGF and trk receptor tyrosine kinases, respectively, are potent chemotactic agents for vascular SMC. Cellular migration is highly regulated, requiring first, the detachment of cells from the extracellular matrix, followed by the reorganization of the cytoskeleton, and finally, the release of matrix, metalloproteinases, to degrade the basement membrane and permit SMC to egress from the media into the intima. The signaling mechanisms which coordinate the complex processes of cellular detachment, cytoskeletal reorganization and MMP release are poorly defined. The overall aim of this proposal is to dissect the downstream pathways regulating SMC migration in response to the neurotrophins and PDGF, and thus, determine if cellular or complementary signaling mechanisms are utilized by these two different receptor tyrosine kinases to induce directed cell migration. Specifically, we plan to: I. Identify signaling pathways activated by growth factors and adhesion molecules which initiate cellular detachment, cytoskeletal reorganization and turnover t focal adhesions in response to migratory stimuli. II. Identify the contributions of metalloproteinases in growth factor-initiate SMC migration. III. Directly evaluate the role of the neurotrophin, BDNF, on lesion development in well defined models of vascular injury. Lesion development in Apo E (-/-) mice deficient in either BDNF or the BDNF receptor, trk B, will be studied chronically in mice maintained on a high fat diet and acutely using the flow dependent-carotid artery ligation model off vascular injury. These studies will allow us to test whether impaired BDNF:trk B signaling reduces neointimal formation. These studies involve critical interactions with Dr. Roy Silverstein (Project III), Dr. Kathy Hajjar (Project II) and Dr. David Hajjar (Project VI).