The microRNA-30 family targets DLL4 to modulate endothelial cell behavior during angiogenesis
- Authors
- Bridge, G., Monteiro, R., Henderson, S., Emuss, V., Lagos, D., Georgopoulou, D., Patient, R., and Boshoff, C.
- ID
- ZDB-PUB-121102-21
- Date
- 2012
- Source
- Blood 120(25): 5063-5072 (Journal)
- Registered Authors
- Patient, Roger K.
- Keywords
- none
- MeSH Terms
-
- Zebrafish/embryology
- Host-Pathogen Interactions
- Herpesvirus 8, Human/physiology
- Intracellular Signaling Peptides and Proteins/genetics*
- Intracellular Signaling Peptides and Proteins/metabolism
- Humans
- Up-Regulation
- Base Sequence
- Embryo, Nonmammalian/blood supply
- Embryo, Nonmammalian/metabolism
- MicroRNAs/genetics*
- MicroRNAs/metabolism
- Neovascularization, Physiologic*
- Human Umbilical Vein Endothelial Cells
- Cell Line
- Endothelial Cells/cytology*
- Endothelial Cells/metabolism
- Endothelial Cells/virology
- Animals
- Gene Expression Regulation, Developmental
- Vascular Endothelial Growth Factor A/genetics
- Herpesviridae Infections/virology
- Membrane Proteins/genetics*
- Membrane Proteins/metabolism
- PubMed
- 23086751 Full text @ Blood
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 upregulated dll4 and synergized with Vegfa signaling knockdown to inhibit angiogenesis. Furthermore, restoration of miR-30b or -30c expression during Kaposi's 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.