MOLECULAR AND CELLULAR CONTROL OF ANGIOGENESIS

摘要 随着原始血管网络的扩张，内皮细胞(EC)对信号输入产生不同的细胞反应 萌芽中的血管生成。这种细胞行为的异质性是通过Key的差异信号来实现的 血管内皮生长因子-A和骨形态发生蛋白等通路。潜在的信号差异是EC在基因水平上的异质性 表达和翻译后蛋白的调控。我们将EC的异质性定义为在 对分子或机械信号的反应，伴随着表达谱和调控的变化 关键途径调节因子。我的实验室帮助理解了血管内皮生长因子-A和骨形态发生蛋白信号如何在 EC的异质性以及Notch如何协调这些途径。当血管对流动做出反应时，异质性就会消失 在生理过程中，介导的信号和重塑以及血管“重新激活”以萌芽和形成新的网络 伤口愈合。这些观察引出了几个问题，这些问题的答案将影响我们的基本理解 血管形成和功能的研究，并有助于了解心血管疾病。我们未来的目标是 研究发育中EC的异质性，检查异质性是如何随着血管重构而消失的 动态平衡，并检验新的假设，即重新激活发育中的EC异质性有助于 伤口愈合血管生成。我们将使用我们开发并成功使用的模型和工具 并且还采用了新的最先进的方法和工具，以将我们的发现的影响扩展到 早期萌发的血管生成。我们的总体假设是，EC的异质性是由低或不存在促进的 流体诱导的剪应力，当剪应力达到临界阈值(S)时，通过 信号通路的调控。我们进一步认为，伤口愈合血管生成是通过减少剪切力来促进的。 应激下游炎症诱导的曲折血管形成。我们将重点介绍血管内皮细胞生长因子的各自作用- A和BMP信号在这些过程中的作用。这一新知识将填补我们关于EC如何实现的关键知识空白 实现从异质产出到动态平衡再到再激活的这一显着转变。这一新知识， 反过来，将使我们和其他人能够更准确地检查EC过渡的失调是如何导致 疾病。

ABSTRACT Endothelial cells (EC) mount distinct cellular responses to signaling inputs as primitive vessel networks expand via sprouting angiogenesis. This heterogeneity in cellular behaviors is achieved by differential signaling of key pathways such as VEGF-A and BMP. Underlying differences in signaling is EC heterogeneity at the level of gene expression and post-translational protein regulation. We define EC heterogeneity as distinct cellular behaviors in response to either molecular or mechanical signals, accompanied by variation in expression profiles and regulation of key pathway regulators. My lab has contributed to understanding how VEGF-A and BMP signaling contribute to EC heterogeneity and how Notch co-ordinates these pathways. Heterogeneity is lost as vessels respond to flow- mediated signals and remodel, and vessels “reactivate” to sprout and form new networks during physiological wound healing. These observations lead to several questions whose answers will impact our basic understanding of blood vessel formation and function, and help understand cardiovascular diseases. Our goals going forward are to investigate developmental EC heterogeneity, to examine how heterogeneity is lost as vessels remodel to homeostasis, and to test the novel hypothesis that reactivation of developmental EC heterogeneity contributes to wound healing angiogenesis. We will use both models and tools that we've developed and successfully used to date, and also incorporate new state-of-the-art approaches and tools to extend the impact of our findings beyond early sprouting angiogenesis. Our over-arching hypothesis is that EC heterogeneity is promoted by low or absent flow-induced shear stress, and repressed when shear stress reaches a critical threshold(s) by transitions in regulation of signaling pathways. We further posit that wound healing angiogenesis is promoted by reduced shear stress downstream inflammation-induced tortuous vessel formation. We will focus on the respective roles of VEGF- A and BMP signaling in these processes. This new knowledge will fill critical gaps in our knowledge of how EC achieve this remarkable transition from heterogeneous outputs to homeostasis to reactivation. This new knowledge, in turn, will allow us and others to examine more precisely how dysregulation of EC transitions contributes to disease.