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Proc Natl Acad Sci U S A. 2015 Oct 13;112(41):12812-7. doi: 10.1073/pnas.1507094112. Epub 2015 Sep 28.

Endothelial miR-17∼92 cluster negatively regulates arteriogenesis via miRNA-19 repression of WNT signaling.

Author information

1
Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520;
2
Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520; Yale Cardiovascular Research Center, Department of Internal Medicine (Cardiology), Yale University School of Medicine, New Haven, CT 06520;
3
miRagen Therapeutics, Boulder, CO 80301.
4
Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520; william.sessa@yale.edu.

Abstract

The contribution of endothelial-derived miR-17∼92 to ischemia-induced arteriogenesis has not been investigated in an in vivo model. In the present study, we demonstrate a critical role for the endothelial-derived miR-17∼92 cluster in shaping physiological and ischemia-triggered arteriogenesis. Endothelial-specific deletion of miR-17∼92 results in an increase in collateral density limbs and hearts and in ischemic limbs compared with control mice, and consequently improves blood flow recovery. Individual cluster components positively or negatively regulate endothelial cell (EC) functions in vitro, and, remarkably, ECs lacking the cluster spontaneously form cords in a manner rescued by miR-17a, -18a, and -19a. Using both in vitro and in vivo analyses, we identified FZD4 and LRP6 as targets of miR-19a/b. Both of these targets were up-regulated in 17∼92 KO ECs compared with control ECs, and both were shown to be targeted by miR-19 using luciferase assays. We demonstrate that miR-19a negatively regulates FZD4, its coreceptor LRP6, and WNT signaling, and that antagonism of miR-19a/b in aged mice improves blood flow recovery after ischemia and reduces repression of these targets. Collectively, these data provide insights into miRNA regulation of arterialization and highlight the importance of vascular WNT signaling in maintaining arterial blood flow.

KEYWORDS:

arteriogenesis; endothelium; microRNA; vascular

PMID:
26417068
PMCID:
PMC4611600
DOI:
10.1073/pnas.1507094112
[Indexed for MEDLINE]
Free PMC Article

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