EGFL7 governs angiogenesis by regulation of vascular Notch singaling

血管发育中一个令人兴奋但仍未解决的话题是管状形成的机制。目前已知的小管生成调节因子很少，但最近的研究表明，一种由内皮细胞分泌的被称为表皮生长因子样域7(EGFL7)的蛋白是一种小管生成因子。遗传学证据表明，Egfl7对血管形成是必不可少的，但尚不清楚EGFl7如何在分子水平上发挥作用，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本身影响血管新生萌发。我们发现EGFL7是Notch受体的一个新的配体，并证明了该蛋白调节干细胞的自我更新潜力和分化模式。此外，我们还将其定位于内皮细胞的细胞外基质中，作为血管整合素ανβ-3的特异性底物。在接下来的三年里，我们打算完成对EGFL7在血管生成中作用的研究，特别是我们将详细研究EGFL7对内皮细胞Notch信号的影响。此外，我们将分析EGFL7如何协调Notch和整合素信号来调节其促血管生成作用。最后，我们将使用EGFL7基因敲除小鼠和EGFL7转基因小鼠在体内验证我们的发现。我期望我们对EGFL7的研究将有助于理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.