Microvascular remodeling in development

描述（由申请人提供）：本申请的重点是通过Akt/PKB激活内皮细胞存活途径在发育性血管生成中的作用。在先前的研究中，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。我们特别强调了VEGF-A在视网膜和肿瘤血管重建中提供存活的作用。基于初步数据和已发表的研究，我们提出了一种假设，即生存信号首先通过稳定血管组装来决定血管形态发生，然后通过控制血管重塑来决定血管形态发生。发芽和血管组装的过程决定了血管将在哪里形成，重塑决定了最终的结构。重塑是将未成熟的血管丛（以早期卵黄囊和早期视网膜血管为代表）转变为由血管周围支持细胞和高度有序、异质性的大小和形状适当的动脉和静脉血管网络组成的完全成熟的器官的分化过程。可溶性因子（如VEGF-A）是未成熟血管存活直到周细胞形成所必需的。为了验证这一整体假设，我们设计了两个目标来解决以下相关主题：第一个目标集中在内皮Akt存活信号对血管发育早期阶段的控制，即血管组装和发芽。第二项研究的重点是组成型活性Akt控制正常发育微血管重塑的能力。因此，在细胞和分子水平上，我们建议探索内皮细胞生存信号在正常发育过程中控制血管形态发生的复杂过程。

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.