The Fat1 Cadherin and Vascular Remodeling

描述（由申请人提供）：Fat 1钙粘蛋白和血管重塑摘要：了解的因素，管理血管重塑，一个过程中的发病机制的临床重要的血管疾病，如动脉粥样硬化，再狭窄，隐静脉移植闭塞，移植动脉硬化，是不完整的。我们最近发现，原钙粘蛋白脂肪1表达的血管平滑肌细胞（VSMC）在多种模型的血管疾病，我们的工作，以及其他人的报告，使我们假设，脂肪1对血管重塑有重要影响。人Fat 1是一种非常大的细胞表面蛋白，由4178个氨基酸的胞外结构域、24个氨基酸的跨膜区和387个氨基酸的胞内结构域组成。非血管系统研究人员的研究表明，脂肪蛋白参与调节细胞骨架重塑和细胞增殖、迁移和极化。最近的研究结果表明，Fat 1的胞内结构域可以与Ena/VASP蛋白，这是已知的参与调节细胞骨架动力学，细胞迁移和增殖。我们已发表的研究表明，Fat 1的表达上调血管重塑中重要的生长因子和细胞因子，包括血管紧张素II，bFGF和PDGF-BB。尽管如此，Fat 1的细胞内结构域的过表达降低了VSMC的生长，这表明Fat 1在血管重塑过程中负调控VSMC。此外，Fat 1表达的抑制显着增强细胞生长，同时限制迁移，表明Fat 1整合VSMC的生长和迁移活性，限制前者，同时促进后者。我们的工作还表明，Fat 1是通过切割加工的，Fat 1细胞内结构域在细胞核中积累，并且它与强大的转录活性相关。为了进一步了解Fat 1在VSMC生物学和血管重塑中的作用，我们建议定义细胞内和细胞外Fat 1如何介导VSMC活性的变化，并确定Fat 1在体内血管重塑中的重要性。由于Fat 1的表达在血管重塑中被诱导，并且由于它对VSMC的生长和迁移具有实质性影响，因此更好地了解其分子功能可能会导致血管疾病的新治疗方法。公共卫生相关性：导致心肌梗塞、中风和血液循环不良的血管疾病仍然是我们社会中死亡、残疾和医疗保健费用的最大原因。我们的工作解决了新的分子机制，可能会控制动脉细胞和动脉壁结构的变化，最终导致血管阻塞和疾病。这些在细胞培养和相关小鼠模型中的研究可能会导致新的预防和治疗方法。

DESCRIPTION (provided by applicant): The Fat1 cadherin and vascular remodeling Abstract: Understanding of the factors that govern vascular remodeling, a process central to the pathogenesis of clinically important vascular diseases such as atherosclerosis, restenosis, saphenous vein graft occlusion, and transplant arteriosclerosis, is incomplete. We recently found that the protocadherin Fat1 is expressed by vascular smooth muscle cells (VSMC) in multiple models of vascular disease, and our work, together with reports from others, lead us to hypothesize that Fat1 has important effects on vascular remodeling. Human Fat1, an extremely large cell surface protein, consists of a 4178 aa extracellular domain, a single 24 aa transmembrane region, and a 387 aa intracellular domain. Studies by investigators working in non-vascular systems have shown that Fat proteins are involved in regulation of cytoskeletal remodeling and cellular proliferation, migration, and polarization. Recent findings indicate that the Fat1 intracellular domain can interact with Ena/VASP proteins, which are known to be involved in regulation of cytoskeletal dynamics, cell migration and proliferation. Our published studies indicate that Fat1 expression is upregulated by growth factors and cytokines important in vascular remodeling, including angiotensin II, bFGF, and PDGF-BB. Despite this observation, overexpression of the intracellular domain of Fat1 reduces growth of VSMCs, which suggests that Fat1 negatively regulates VSMCs during vascular remodeling. Moreover, inhibition of Fat1 expression significantly potentiates cell growth while limiting migration, indicating that Fat1 integrates VSMC growth and migration activity in limiting the former while facilitating the latter. Our work shows also that Fat1 is processed by cleavage, that the Fat1 intracellular domain accumulates in the cell nucleus, and that it associates with robust transcriptional activity. To further our understanding of the role of Fat1 in VSMC biology and vascular remodeling, we propose to define how both intracellular and extracellular Fat1 mediate changes in VSMC activity, and to determine the importance of Fat1 in vascular remodeling in vivo. Because Fat1 expression is induced in vascular remodeling, and because it has substantial effects on VSMC growth and migration, better understanding of its molecular functions may lead to novel therapeutic approaches for vascular diseases. PUBLIC HEALTH RELEVANCE: Vascular diseases that cause myocardial infarction, stroke, and poor circulation remain the greatest cause of death, disability, and health care expense in our society. Our work addresses novel molecular mechanisms that may govern the changes in arterial cells and artery wall structure that eventually result in vascular obstruction and disease. These studies in cell culture and relevant mouse models may lead to new approaches for prevention and treatment.