The Fat1 Cadherin and Vascular Remodeling

描述(申请人提供)：Fat1钙粘附素与血管重塑摘要：对控制血管重塑的因素的了解尚不完整，血管重塑是动脉粥样硬化、再狭窄、隐静脉移植物闭塞和移植物动脉硬化等临床重要血管疾病发病机制的核心过程。我们最近发现，在多种血管疾病模型中，血管平滑肌细胞(VSMC)表达原钙粘附素Fat1，我们的工作与其他人的报道一起，使我们假设Fat1在血管重塑中具有重要作用。人Fat1是一个极大的细胞表面蛋白，由4178个氨基酸的胞外区、一个24个氨基酸的跨膜区和一个387个氨基酸的胞内区组成。在非血管系统工作的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的增殖、迁移和极化。最近的研究表明，Fat1的胞内结构域可以与Ena/Vasp蛋白相互作用，后者被认为参与了细胞骨架动力学、细胞迁移和增殖的调节。我们已发表的研究表明，Fat1的表达受到血管重塑中重要的生长因子和细胞因子的上调，包括血管紧张素II、碱性成纤维细胞生长因子和PDGF-BB。尽管如此，Fat1细胞内域的过度表达减少了VSMCs的生长，这表明Fat1在血管重塑过程中负向调节VSMCs。此外，抑制Fat1的表达显著增强了细胞的生长，同时限制了迁移，表明Fat1整合了VSMC的生长和迁移活性，限制了前者，而促进了后者。我们的工作还表明，Fat1是通过切割来处理的，Fat1的胞内结构域积累在细胞核中，并且它与强大的转录活性有关。为了进一步了解Fat1在VSMC生物学和血管重塑中的作用，我们建议确定细胞内和细胞外Fat1如何介导VSMC活性的变化，并确定Fat1在体内血管重塑中的重要性。由于Fat1在血管重塑过程中被诱导表达，并且对VSMC的生长和迁移有重要影响，对其分子功能的深入了解可能会为血管疾病的治疗提供新的途径。公共卫生相关性：导致心肌梗死、中风和循环不良的血管疾病仍然是我们社会死亡、残疾和医疗费用的最大原因。我们的工作解决了新的分子机制，可能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带来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.