EGFL7 governs angiogenesis by regulation of vascular Notch singaling

一个令人兴奋的和仍然悬而未决的主题在血管发育是管形成的机制。只有少数调控微管发生的是已知的，但最近的研究表明，由内皮细胞分泌的蛋白质，并称为表皮生长因子样结构域7（EGFL7）是一个微管发生因子。遗传学证据表明egfl7对血管形成至关重要，但目前尚不清楚EGFL7如何在分子水平上起作用以及该蛋白质如何介导其生物学效应。在之前的资助期间，我们能够证明EGFL7本身会影响血管生成发芽。我们将EGFL7鉴定为Notch受体的新型配体，并证明该蛋白质调节干细胞的自我更新潜力和分化模式。此外，我们将EGFL7定位在内皮细胞的细胞外基质（ECM）中，在那里它充当血管整联蛋白ανβ3的特异性底物。EGFL7的细胞外相互作用为其对血管生成的作用提供了分子解释。在接下来的三年里，我们打算完成我们对EGFL7在血管生成中的作用的研究，特别是，我们将详细研究EGFL7对内皮细胞中Notch信号传导的影响。此外，我们将分析EGFL7如何协调Notch和整合素信号传导来介导其促血管生成作用。最后，我们将使用EGFL7敲除小鼠和EGFL7转基因小鼠来验证我们的体内研究结果。我预计，我们对EGFL7的研究将有助于了解脊椎动物血管形成的分子机制。

An exciting and still unresolved topic in vascular development is the mechanism governing tube formation. Only a few regulators of tubulogenesis are known but recent studies indicated that a protein secreted by endothelial cells and termed epidermal growth factor-like domain 7 (EGFL7) is a tubulogenesis factor. Genetic evidence suggested egfl7 is essential for vascular tube formation, but it was not known how EGFL7 acts on the molecular level and how the protein mediates its biological effects. In the previous funding period, we were able to show that EGFL7 affects angiogenic sprouting per se. We identified EGFL7 as a novel ligand of Notch receptors and demonstrated that the protein regulates the self-renewal potential and differentiation pattern of stem cells. Further, we located EGFL7 in the extracellular matrix (ECM) of endothelial cells, where it serves as a specific substrate for the vascular integrin ανβ3. The extracellular interactions of EGFL7 delivered a molecular explanation for its effects on angiogenesis. In the next three years, we intend to complete our studies on the role of EGFL7 in angiogenesis and in particular, we will study the effects of EGFL7 on Notch signaling in endothelial cells in detail. Further, we will analyze how EGFL7 orchestrates Notch and integrin signaling to mediate its proangiogenic effects. Last, we will use EGFL7 knock-out mice and EGFL7 transgenic mice to validate our findings in vivo. I anticipate that our studies on EGFL7 will contribute to the understanding of the molecular mechanisms governing vascular tube formation in vertebrates.