Beta-catenin in vascular homeostasis and remodeling

经典Wnt/β-连环蛋白(β-CTn)信号转导在胚胎发育中的重要作用 许多成人组织的发育和动态平衡。条件失活β-cTn， 途径活性的唯一下游介体，在多个方面证明了它的必要性 活体内的不同过程。内皮细胞(ECs)中β-cTn的失活，例如， 导致胚胎血管缺陷局限于中枢神经系统，而全身性 血管发育看起来很正常。有趣的是，我们最近的研究表明 小鼠血管平滑肌细胞β-cTn失活通过以下途径导致死亡 胚胎期(E)12.5天，体动脉扩张，因以下原因而功能不全 损害SMC的增殖、存活和发育中的血管壁的投资。 因此，在发育过程中，体循环的SMC需要β-CTN的表达， 而相应的欧洲共同体则不会。我们的机制分析表明，前者 影响部分取决于来自β-CTN C-末端结构域的关键信号，这些信号抑制 肿瘤抑制基因P53的乙酰化和活性。 β-cTn在成人血管系统中的功能及其在血管动态平衡中的潜在作用 重塑还没有被很好地理解。我们的初步研究表明，SMCβ-CTN 可以在成年小鼠身上灭活而不会立即造成血管后果，但 血管损伤后新生内膜的形成因其缺失而显著减少。 抑制β-cTn如何影响成人血管完整性、损伤反应和 动脉粥样硬化尚未见报道。我们在理解上的这些差距是显著的， 因为β-cTn信号的异常与多发性硬化的发病机制有关 癌症，因此抑制β-cTn是几个潜在的重要靶 新兴的抗肿瘤策略。这项建议包括三个目标：第一， 确定β-CTN是如何抑制SMC P53活性的，第二，评估β-CTN的结构和 N-vs C-末端信号转导在血管内稳态、损伤反应和 第三，测试Wnt/β-cTn抑制作为一种潜在的治疗策略 用于控制加速的血管重塑和/或动脉粥样硬化。 分析β-cTn在血管功能中的作用有助于了解新的治疗方法 基于WNT/β-CTN的抑制可能会影响血管的动态平衡，应该允许我们 评价这些方法的安全性及其在血管治疗中的潜在效用 疾病。

Canonical Wnt/beta-catenin (β-ctn) signaling plays a crucial role in embryonic development and homeostasis of many adult tissues. Conditional inactivation of β-ctn, the sole downstream mediator of pathway activity, demonstrates its necessity in multiple diverse processes in vivo. Inactivation of β-ctn in endothelial cells (ECs), for example, yields embryonic vascular defects limited to the central nervous system, while systemic vascular development appears normal. Interestingly, our recent studies show that inactivation of β-ctn in vascular smooth muscle cells (SMCs) in mice causes death by embryonic day (E) 12.5, with systemic arteries that are dilated and incompetent due to impaired SMC proliferation, survival, and investment of the developing vascular wall. Thus during development, SMCs of the systemic circulation require β-ctn expression, while corresponding ECs do not. Our mechanistic analysis indicates that the former effect depends in part on critical signals from the β-ctn C-terminal domain that suppress acetylation and activity of the tumor suppressor p53. β-ctn functions in the adult vasculature and its potential roles in vascular homeostasis or remodeling are not well understood. Our preliminary studies indicate that SMC β-ctn can be inactivated in the adult mouse without immediate vascular consequences, but that neointimal formation after vascular injury is significantly reduced by its absence. How β-ctn inhibition affects adult vascular integrity, response to injury, and atherosclerosis has not been reported. These gaps in our understanding are significant, because aberrant β-ctn signaling has been implicated in the pathogenesis of multiple cancers, and thus inhibition of β-ctn serves as a potentially important target in several emerging anti-neoplastic strategies. This proposal encompasses three aims: first, to determine how β-ctn suppresses SMC p53 activity, second, to assess β-ctn structural and N- vs C-terminal signaling functions in vascular homeostasis, injury response, and atherosclerosis, and third, to test Wnt/β-ctn inhibition as a potential therapeutic strategy for control of accelerated vascular remodeling and/or atherosclerosis. Analysis of β-ctn in vascular function is relevant to understanding how new therapies based on Wnt/β-ctn inhibition may affect vascular homeostasis, and should allow us to evaluate the safety of such approaches and their potential utility in treatment of vascular disease.