PUBLICATION

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
  • Animals
  • Arterioles/metabolism*
  • Basic Helix-Loop-Helix Transcription Factors/genetics
  • Basic Helix-Loop-Helix Transcription Factors/metabolism
  • Cell Communication/physiology
  • Cell Shape/physiology*
  • Endothelial Cells/cytology
  • Endothelial Cells/metabolism*
  • Ephrin-B2/genetics
  • Ephrin-B2/metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins/genetics
  • Intracellular Signaling Peptides and Proteins/metabolism
  • Membrane Proteins/genetics
  • Membrane Proteins/metabolism
  • MicroRNAs/genetics
  • MicroRNAs/metabolism*
  • Neovascularization, Physiologic/physiology*
  • Receptors, Notch/metabolism
  • Repressor Proteins/genetics
  • Repressor Proteins/metabolism
  • Signal Transduction/physiology*
  • Zebrafish
PubMed
23817492 Full text @ Hypertension
Abstract

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.

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Errata and Notes