Vascular Growth and Regeneration

项目说明/摘要 我们关于血管生长的许多集体知识都是从理解血管生成的努力中产生的， 血管内皮细胞脱离原有血管形成新的血管床的过程。 尽管如此，一旦形成，血管也会在宽度、长度上扩张，并能够再生。 再生对于修复支架和其他组织造成的内皮损伤极其重要。 医疗设备，以及在物理/化学创伤后调解愈合。然而，我们对 调控血管内皮细胞生长和再生的细胞和分子机制 全功能、血液灌流和搏动的血管是有限的。我们的初步数据显示， 体内内膜的扩张是通过血管内皮细胞的固有增殖来实现的。 两极分化和有组织的方式。事实上，伤口两侧的内皮细胞亚群被强有力地诱导 以高度同步的方式在受伤后最快12小时进入细胞周期。这个 这个过程是由细胞-细胞连接的变化启动的，这种变化触发了分子重新连接，给人留下了深刻的印象 生理变化。这些反应的重要结果包括内皮细胞的改变 极性，染色质重塑的诱导，新陈代谢的调整和快速的 再生内皮所特有的转录信号。这个新识别的签名很好 通过压力信号的定时释放进行调节，这些压力信号似乎在内皮细胞的亚群中起不同的作用 细胞，揭示了一种内在的异质性，控制着给定血管再生的门槛。在……里面 事实上，使用内皮特异的彩虹小鼠进行的遗传追踪分析揭示了具有 不同的增殖潜能提示前体细胞嵌入内皮细胞壁内 单层。综上所述，这些研究正在转变理解机制的范式 在慢性/急性炎症等环境中控制内皮再生及其放松调控， 老龄化、慢性病和身体创伤。 通过NHLBI杰出研究员奖的申请，我们的目标是(1)解码蜂窝和 控制血管内皮细胞扩张过程的分子机制；(2)阐明 涉及内皮再生和修复的过程：(3)了解劫持这些 机制可能加速或损害内皮再生；(4)确定新的靶点 针对支架植入或其他损伤过程中的内皮修复的治疗干预。这些系列 广泛定义的目标已经被概念化，以填补我们在基础生物学知识方面的空白 内皮细胞生物学的过程，也是利用这些信息在医学上的应用 支架覆盖等干预措施。我们为这笔赠款提供的机会而感到振奋 机制以及这些研究的潜在翻译影响。

PROJECT DESCRIPTION / SUMMARY Much of our collective knowledge on vascular growth has emerged from efforts to understand angiogenesis, a process by which endothelial cells depart from pre-existent vessels to form new vascular beds. Nonetheless, once formed, vascular tubes also expand in width, length, and are able to regenerate. Regeneration is extremely important to the repair of endothelial damage imposed by stents and other medical devises, as well as to mediate heal after physical/chemical trauma. However our understanding of the cellular and molecular mechanisms that regulate endothelial growth and regeneration within the context of a fully functional, blood perfused and pulsatile vessel are limited. Our preliminary data show that expansion of the tunica intima in vivo occurs through intrinsic proliferation of intimal endothelial cells in a polarized and organized manner. In fact, a subset of endothelial cells flanking a wound are robustly induced to enter into the cell cycle as quickly as 12 hours following injury in a highly synchronized fashion. The process is initiated by changes in cell-cell junctions that trigger molecular rewiring and impressive physiological changes. Important outcomes of these responses include alterations in endothelial cell polarity, induction of chromatin remodeling, adjustments in metabolism and a quick emergence of a transcriptional signature that is unique to regenerative endothelium. This newly identified signature is finely tuned by the timed release of stress signals that appear to act differentially in the subsets of endothelial cells, revealing an intrinsic heterogeneity that controls the threshold for regeneration in a given vessel. In fact, genetic tracing analysis using endothelial-specific rainbow mice revealed the presence of cells with different proliferative potential suggesting the intercalation of progenitors within the wall of the endothelial monolayer. Taken together, these studies are paradigm shifting for understanding the mechanisms controlling endothelial regeneration and their deregulations in settings like chronic/acute inflammation, aging, chronic diseases and physical trauma. Through this NHLBI Outstanding Investigator Award application our goals are to (1) decode the cellular and molecular mechanisms controlling the process of endothelial expansion within a formed vessel; (2) clarify the process involved in endothelial regeneration and repair: (3) understand how hijacking these mechanisms might either accelerate or impair endothelial regeneration; (4) identify novel targets for therapeutic interventions aimed at endothelial repair during stenting or other injuries. These series of broadly defined aims have been conceptualize to fill gaps of our knowledge on fundamental biological processes in endothelial cell biology but also to exploit this information for application during medical interventions such as stent coverage. We are energized by the opportunity afforded by this grant mechanism and for the potential translational impact of these studies.