EGFL7 governs angiogenesis by regulation of vascular Notch singaling

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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.