Delta-like 4 (DLL4), a membrane-bound ligand belonging to the Notch signaling family, plays a fundamental role in vascular development and angiogenesis. We identified a conserved microRNA family, miR-30, which targets DLL4. Overexpression of miR-30b in endothelial cells led to increased vessel number and length in an in vitro model of sprouting angiogenesis. Microinjection of miR-30 mimics into zebrafish embryos resulted in suppression of dll4 and subsequent excessive sprouting of intersegmental vessels and reduction in dorsal aorta diameter. Use of a target protector against the miR-30 site within the dll4 3'UTR up-regulated dll4 and synergized with Vegfa signaling knockdown to inhibit angiogenesis. Furthermore, restoration of miR-30b or miR-30c expression during Kaposi sarcoma herpesvirus (KSHV) infection attenuated viral induction of DLL4. Together these results demonstrate that the highly conserved molecular targeting of DLL4 by the miR-30 family regulates angiogenesis.
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Animals, Base Sequence, Cell Line, Embryo, Nonmammalian, Endothelial Cells, Gene Expression Regulation, Developmental, Herpesviridae Infections, Herpesvirus 8, Human, Host-Pathogen Interactions, Human Umbilical Vein Endothelial Cells, Humans, Intracellular Signaling Peptides and Proteins, Membrane Proteins, MicroRNAs, Neovascularization, Physiologic, Up-Regulation, Vascular Endothelial Growth Factor A, Zebrafish