miR-30a Regulates Endothelial Tip Cell Formation and Arteriolar Branching
- Authors
- Jiang, Q., Lagos-Quintana, M., Liu, D., Shi, Y., Helker, C., Herzog, W., and le Noble, F.
- ID
- ZDB-PUB-130710-115
- Date
- 2013
- Source
- Hypertension (Dallas, Tex. : 1979) 62(3): 592-8 (Journal)
- Registered Authors
- Helker, Christian, Herzog, Wiebke, Jiang, Qiu, le Noble, Ferdinand
- Keywords
- angiogenesis, microRNAs, Notch receptors
- MeSH Terms
-
- Arterioles/metabolism*
- Zebrafish
- Ephrin-B2/genetics
- Ephrin-B2/metabolism
- Membrane Proteins/genetics
- Membrane Proteins/metabolism
- Intracellular Signaling Peptides and Proteins/genetics
- Intracellular Signaling Peptides and Proteins/metabolism
- Humans
- Signal Transduction/physiology*
- Endothelial Cells/cytology
- Endothelial Cells/metabolism*
- Basic Helix-Loop-Helix Transcription Factors/genetics
- Basic Helix-Loop-Helix Transcription Factors/metabolism
- Repressor Proteins/genetics
- Repressor Proteins/metabolism
- Cell Communication/physiology
- Cell Shape/physiology*
- Receptors, Notch/metabolism
- Animals
- MicroRNAs/genetics
- MicroRNAs/metabolism*
- Neovascularization, Physiologic/physiology*
- PubMed
- 23817492 Full text @ Hypertension
Microvascular rarefaction increases vascular resistance and pressure in systemic arteries and is a hallmark of fixed essential hypertension. Preventing rarefaction by activation of angiogenic processes could lower blood pressure. Endothelial tip cells in angiogenic sprouts direct branching of microvascular networks; the process is regulated by microRNAs, particularly the miR-30 family. We investigated the contribution of miR-30 family members in arteriolar branching morphogenesis via delta-like 4 (Dll4)-Notch signaling in a zebrafish model. The miR-30 family consists of 5 members (miR-30a-e). Loss-of-function experiments showed that only miR-30a reduced growth of intersegmental arterioles involving impaired tip cell function. Overexpression of miR-30a stimulated tip cell behavior resulting in augmented branching of intersegmental arterioles. In vitro and in vivo reporter assays showed that miR-30a directly targets the Notch ligand Dll4, a key inhibitor of tip cell formation. Coadministration of a Dll4 targeting morpholino in miR-30a morphants rescued the branching defects. Conversely, conditional overexpression of Notch intracellular domain restored arteriolar branching in miR-30a gain-of-function embryos. In human endothelial cells, loss of miR-30a increased DLL4 protein levels, activated Notch signaling as indicated in Notch reporter assays, and augmented Notch downstream effector, HEY2 and EFNB2 (ephrin-B2), expression. In spheroid assays, miR-30a loss- and gain-of-function affected tip cell behavior, consistent with miR-30a targeting Dll4. Our data suggest that miR-30a stimulates arteriolar branching by downregulating endothelial Dll4 expression, thereby controlling endothelial tip cell behavior. These findings could have relevance to the rarefaction process and, therefore, to hypertension.