Cytokine Regulation of Early Events in Blood Vessel Form

描述（由申请人提供）：血管发生是从中胚层重新形成血管。血管发生的基本步骤是未分化的中胚层生成成血管细胞，成血管细胞合并并转化为内皮细胞（ECs）。此外，我们的研究还揭示了该过程的后续步骤，即小血管融合形成大血管和血管窦。这个过程被称为血管融合，是在实验中发现的，在实验中，VEGF水平升高会导致不受控制的融合，即低灌注。vegf诱导的低灌注不仅在多个物种的胚胎中被描述，而且在成人新生血管过程中也很重要。事实上，不受控制的融合活性现在是VEGF众多治疗用途的障碍。了解控制血管融合的机制一直是我们研究的重点。结果发现VEGF/VEGF受体对融合和低灌注至关重要，内皮细胞密度与特定血管形态存在相关关系。基于这些和其他发现，我们提出了EC数量/密度的调节是正常血管融合和低灌注病理过程的基础。影响EC数量/密度的主要途径包括控制有丝分裂、凋亡和/或中胚层EC祖细胞的募集。本应用程序中概述的实验将确定VEGF- a （VEGF165/VEGFt21）和PLGF信号通过VEGF受体（Flkl， Fltl和Neuropilin 1 & 2）影响血管形态发生并调节EC数量/密度的形态学后果和机制。关于祖细胞在血管发生部位的募集，我们还将扩展我们的初步发现，表明循环胚胎干细胞有助于血管发生和血管融合。提出的研究计划的一个主要优势是使用了我们已经建立的体内鸟类实验和一个强大的新的体外小鼠血管生成模型，该模型概括了体内血管生成的重要方面。该研究有望有助于更好地理解血管发生、血管融合和低灌注，并为针对各种疾病的新血管成分的策略提供新的视角。

DESCRIPTION (provided by applicant): Vasculogenesis is the de novo formation of blood vessels from mesoderm. Basic steps in the process of vasculogenesis are the generation of angioblasts from undifferentiated mesoderm and the coalescence and transformation of angioblasts into endothelial cells (ECs). In addition, our studies have revealed a subsequent step in the process that involves the fusion of small vessels to form large vessels and vascular sinuses. This process, termed vascular fusion, was discovered as a result of experimentation in which elevated levels of VEGF were shown to lead to uncontrolled fusion, hyperfusion. VEGF-induced hyperfusion has not only been described in embryos of multiple species, but importantly in adult neovascular processes. Indeed, uncontrolled fusion activity now stands as an impediment to the numerous therapeutic uses envisioned for VEGF. Understanding the mechanism(s) by which vascular fusion is controlled has been a focus of our research. As a result we have found that VEGF/VEGF receptor is critical to fusion and hyperfusion and that a correlative relationship exists between the density of ECs and specific vascular patterns. Based on these and other findings we have derived the hypothesis that regulation of EC numbers/density is fundamental to normal vascular fusion and the pathological process of hyperfusion. Major ways to influence EC numbers/density include control of mitosis, apoptosis and/or recruitment of EC progenitor cells from mesoderm. Experimentation outlined in this application will determine the morphological consequences of and the mechanisms by which VEGF-A (VEGF165/VEGFt21) and PLGF signaling via the VEGF receptors (Flkl, Fltl and Neuropilin 1 & 2) impact vascular morphogenesis and act to regulate EC numbers/density. With respect to recruitment of progenitor cells to sites of vasculogenesis, we will also extend on our preliminary findings indicating that circulating embryonic stem cells contribute to vasculogenesis and vascular fusion. A major strength of the proposed research plan is the use of both our well-established in vivo avian assay and a powerful new in vitro murine model of vasculogenesis that recapitulates salient aspects of in vivo vasculogenesis. The proposed research is expected to contribute to a greater understanding of vasculogenesis, vascular fusion, and hyperfusion and offer new perspectives for strategies that target the neovascular component of various diseases.