MOLECULAR AND CELLULAR CONTROL OF ANGIOGENESIS

摘要 内皮细胞（EC）对信号输入产生不同的细胞反应，因为原始血管网络通过 萌芽血管生成。细胞行为的这种异质性是通过关键信号的差异信号传导实现的。 如VEGF-A和BMP的途径。信号传导的潜在差异是EC在基因水平上的异质性， 表达和翻译后蛋白调节。我们将EC异质性定义为不同的细胞行为， 对分子或机械信号的反应，伴随着表达谱和调节的变化 关键通路调节器。我的实验室有助于了解VEGF-A和BMP信号如何有助于 EC异质性以及Notch如何协调这些途径。当血管对血流做出反应时，异质性就会消失- 介导的信号和重塑，和血管“重新激活”发芽，并在生理过程中形成新的网络， 伤口愈合这些观察结果引出了几个问题，这些问题的答案将影响我们对 血管的形成和功能，并帮助了解心血管疾病。我们未来的目标是 研究发育EC异质性，研究异质性如何随着血管重塑而丧失， 动态平衡，并测试新的假设，即重新激活的发展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， 日期，并纳入新的最先进的方法和工具，以扩大我们的研究结果的影响， 早期萌芽血管生成。我们的过度假设是，EC异质性是由低或缺乏 流动诱导的剪切应力，并在剪切应力达到临界阈值时通过 调节信号通路。我们进一步证实，伤口愈合血管生成是由减少剪切促进 应力下游炎症诱导的曲折血管形成。我们将重点关注VEGF的各自作用- A和BMP信号在这些过程中。这一新知识将填补我们对电子商务如何运作的知识的关键空白。 实现了从异质输出到稳态再到激活的显著转变。这些新知识， 反过来，这将使我们和其他人能够更准确地研究欧共体转型的失调如何有助于 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.