Editors' ChoiceAtherosclerosis

Micro(RNA)managing Endothelial Regeneration

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Science Translational Medicine  02 Apr 2014:
Vol. 6, Issue 230, pp. 230ec57
DOI: 10.1126/scitranslmed.3009173

When seeking a place to perform, the atherosclerotic process both goes with the flow and looks for trouble. Plaques preferentially form at sites in the vascular system that experience disturbed laminar blood flow at arterial branch points and display a dysfunctional endothelium that is exacerbated by hypertension, dyslipidemia, and hyperglycemia. These predilection sites display signs of endothelial cell (EC) death, inflammation, up-regulated adhesion molecules, intimal infiltration of monocytes, and retention of lipoproteins in the arterial wall. Why are these sites predisposed to plaque formation? Now, Schober et al. uncover an unusual suspect—an EC-enriched microRNA (miRNA) that is highly responsive to hemodynamic shear flow stress and acts at these sites to control endothelial regeneration.

The authors set forth to identify molecular cues for endothelial repair in injured arteries and found that vascular ECs contained high amounts of miR-126-5p and miR-126-3p. Deletion of miR-126 from apolipoprotein E–deficient (ApoE–/–) mice led to a significant increase in atherosclerotic lesion size and impairment of EC recovery of the luminal lining after its complete removal, when compared with those of controls. Although miR-126 is also expressed in macrophages, bone marrow chimera experiments revealed that the miR-126–deficient phenotype was independent of the status of bone marrow–derived miR-126. The authors then asked which miR-126 strand regulated endothelial proliferation. Application of strand-specific miRNA inhibitors via perivascular treatment to denuded ApoE–/– arteries revealed that only the miR-126-5p inhibitor increased lesion area and blocked endothelial recovery. An elaborate set of experiments ranging from microarrays to EC-specific gene deletion narrowed the miR-126-5p target to Dlk1, a membrane protein with epidermal growth factor repeats that is an inhibitor of NOTCH1 signaling and EC proliferation in humans. In the new work, disturbed blood flow in mice down-regulated miR-126-5p and up-regulated Dlk1 expression, and Notch1 activity was reduced mainly in ECs in the injured arteries of miR-126–/–, ApoE–/– mice. Dlk1 directly inhibited endothelial recovery and vascular repair both in vitro and in vivo. Last, systemic treatment of the miR-126-5p–/–, ApoE–/– mice (on a hypercholestrolemic diet) with miR-126-5p mimics substantially blocked plaque formation while increasing EC proliferation at the predilection sites.

The recent succesful targeting of the atherogenic miR-33 in both mouse and primates generated dynamic interest in miRNA-based therapeutics for cardiovascular disease. The list of atherogenic miRNAs is growing, but the EC-derived mirR-126-5p stands out because of its singular direct role in vascular endothelial regeneration. The observation that the levels of miR-126-5p but not miR-126-3p were associated with lower Dlk1 amounts in EC in human plaques suggests that systemic therapeutic targeting of miR-126-5p may be successful in the treatment of human atherosclerosis.

A. Schober et al., MicroRNA-126-5p promotes endothelial proliferation and limits atherosclerosis by suppressing Dlk1. Nat. Med. 10.1038/nm.3487 (2014). [Abstract]

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