The Fat1 Cadherin and Vascular Remodeling

摘要：血管重构是临床上重要血管疾病（如动脉粥样硬化、再狭窄、隐静脉移植闭塞和移植动脉硬化）发病机制的核心过程，但对其调控因素的了解尚不完整。我们最近发现原钙粘蛋白Fat1在多种血管疾病模型中由血管平滑肌细胞（VSMC）表达，我们的工作以及其他人的报道使我们假设Fat1在血管重塑中具有重要作用。人Fat1是一种非常大的细胞表面蛋白，由一个4178 aa的胞外结构域、一个24 aa的跨膜区域和一个387 aa的胞内结构域组成。非血管系统研究人员的研究表明，脂肪蛋白参与细胞骨架重塑和细胞增殖、迁移和极化的调节。最近的研究表明，Fat1胞内结构域可以与Ena/VASP蛋白相互作用，而Ena/VASP蛋白参与细胞骨架动力学、细胞迁移和增殖的调节。我们发表的研究表明，在血管重构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，可以上调Fat1的表达。尽管如此，细胞内Fat1结构域的过表达减少了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表达可显著促进细胞生长，同时限制迁移，表明Fat1整合了VSMC生长和迁移活性，限制前者，促进后者。我们的工作还表明，Fat1是通过切割加工的，Fat1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Fat1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的表达在血管重塑中被诱导，并且对VSMC的生长和迁移有实质性影响，因此更好地了解其分子功能可能会为血管疾病的治疗带来新的方法。公共卫生相关性：在我们的社会中，引起心肌梗死、中风和血液循环不良的血管疾病仍然是导致死亡、残疾和医疗费用增加的最大原因。我们的工作涉及可能控制最终导致血管阻塞和疾病的动脉细胞和动脉壁结构变化的新分子机制。这些细胞培养和相关小鼠模型的研究可能为预防和治疗提供新的途径。

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.