Microvascular remodeling in development

描述(由申请人提供)：本申请集中于通过Akt/PKB激活的内皮细胞生存通路在发育血管生成中的作用。在以前的研究中，我们已经阐明了在血管发育的多个阶段激活生存途径的因素。特别是，我们强调了血管内皮生长因子-A在提供存活、重塑视网膜和肿瘤血管方面的作用。基于初步数据和已发表的研究，我们提出了这样的假设：生存信号首先通过稳定血管组装来决定血管的形态发生，然后通过控制重构来决定血管的形态发生。发芽和血管组装的过程决定了血管将在哪里形成，而重塑决定了最终的结构。重建是将未成熟的血管丛(以早期卵黄囊和早期视网膜血管系统为代表)转变为完全成熟的器官的分化过程，由血管周围支持细胞和高度有序且异质的大小和形状合适的动静脉血管网络组成。未成熟的血管需要可溶性因子(如血管内皮生长因子-A)才能存活，直到周细胞包被发生。为了验证这一总体假设，我们设计了两个目标来解决以下相关主题：第一个目标是内皮细胞Akt生存的控制，信号转导到血管发育的最早阶段，即血管组装和萌芽。第二个重点是结构性活性Akt控制正常发育性微血管重构的能力。因此，我们建议在细胞和分子水平上探索内皮细胞生存信号的复杂过程，该信号控制着正常发育过程中的血管形态发生。

DESCRIPTION (provided by applicant): This application is focused on the role of endothelial cell survival pathways via Akt/PKB activation in developmental angiogenesis. In previous studies, we have elucidated factors that activate survival pathways at multiple stages of vascular development. In particular, we highlighted the role of VEGF-A in providing survival remodeling retinal and tumor blood vessels. Based on preliminary data and published studies, we put forth the hypothesis that survival signals determine vascular morphogenesis first by stabilizing vascular assembly, and later by governing remodeling. The processes of sprouting and vessel assembly determine where blood vessels will form, and remodeling determines the final architecture. Remodeling is the differentiation process that transitions the immature vascular plexus (typified by the early yolk sac and early retinal vasculature) into a fully mature organ consisting of perivascular support cells and highly ordered and heterogeneous network of arterial and venous vessels of appropriate sizes and shapes. Soluble factors (such as VEGF-A) are required for the immature blood vessels to survive until pericyte investment occurs. To test this overall hypothesis, we have designed two aims to address the following related topics: the first is centered on the controls of endothelial Akt survival signaling to the earliest phases of blood vessel development, i.e. vessel assembly and sprouting. The second is focused on the ability of constitutively active Akt to control normal developmental microvascular remodeling. Thus, at cellular and molecular levels, we propose to explore the complex process of endothelial cell survival signaling that governs vascular morphogenesis during normal development.