Platelet-derived miR-223 promotes a phenotypic switch in arterial injury repair
Zhi Zeng, … , John Hwa, Wai Ho Tang
Zhi Zeng, … , John Hwa, Wai Ho Tang
Published January 15, 2019
Citation Information: J Clin Invest. 2019;129(3):1372-1386. https://doi.org/10.1172/JCI124508.
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Research Article Vascular biology

Platelet-derived miR-223 promotes a phenotypic switch in arterial injury repair

Abstract

Upon arterial injury, endothelial denudation leads to platelet activation and delivery of multiple agents (e.g., TXA2, PDGF), promoting VSMC dedifferentiation and proliferation (intimal hyperplasia) during injury repair. The process of resolution of vessel injury repair, and prevention of excessive repair (switching VSMCs back to a differentiated quiescent state), is poorly understood. We now report that internalization of APs by VSMCs promotes resolution of arterial injury by switching on VSMC quiescence. Ex vivo and in vivo studies using lineage tracing reporter mice (PF4-cre × mT/mG) demonstrated uptake of GFP-labeled platelets (mG) by mTomato red–labeled VSMCs (mT) upon arterial wire injury. Genome-wide miRNA sequencing of VSMCs cocultured with APs identified significant increases in platelet-derived miR-223. miR-223 appears to directly target PDGFRβ (in VSMCs), reversing the injury-induced dedifferentiation. Upon arterial injury, platelet miR-223–KO mice exhibited increased intimal hyperplasia, whereas miR-223 mimics reduced intimal hyperplasia. Diabetic mice with reduced expression of miR-223 exhibited enhanced VSMC dedifferentiation and proliferation and increased intimal hyperplasia. Our results suggest that horizontal transfer of platelet-derived miRNAs into VSMCs provides a novel mechanism for regulating VSMC phenotypic switching. Platelets thus play a dual role in vascular injury repair, initiating an immediate repair process and, concurrently, a delayed process to prevent excessive repair.

Authors

Zhi Zeng, Luoxing Xia, Xuejiao Fan, Allison C. Ostriker, Timur Yarovinsky, Meiling Su, Yuan Zhang, Xiangwen Peng, Yi Xie, Lei Pi, Xiaoqiong Gu, Sookja Kim Chung, Kathleen A. Martin, Renjing Liu, John Hwa, Wai Ho Tang

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Figure 4

miR-223 modulates Pdgfrβ expression and intimal hyperplasia in vivo after femoral arterial injury.

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miR-223 modulates Pdgfrβ expression and intimal hyperplasia in vivo afte...
(A) Representative immunofluorescence of Pdgfrβ in uninjured or injured femoral arteries from WT mice, and miR-223 KO mice treated with AgomiR-NC or AgomiR-223 at 4 weeks after wire injury (n = 5). Green, Pdgfrβ; blue, DAPI nuclear staining; red, Acta2 in VSMCs. Scale bars: 20 μm. (B) Quantification of Pdgfrβ expression in VSMCs in injured femoral arteries. Data are presented as mean ± SD (n = 5). ***P < 0.001 vs. WT; ###P < 0.001 vs. miR-223 KO mice treated with AgomiR-NC. (C) H&E staining of serial cross sections of femoral arteries from WT mice, and miR-223 KO mice treated with AgomiR-NC or AgomiR-223 at 4 weeks after injury (n = 5). Scale bars: 100 μm. (D) Morphometric measurements of the I/M ratio in the injured femoral arterial sections. Data are presented as mean ± SD of I/M ratio (n = 5). **P < 0.01 vs. WT; ##P < 0.01 vs. miR-223 KO mice treated with AgomiR-NC. Statistical significance was determined using 1-way ANOVA followed by Tukey-Kramer multiple-comparisons test (B and D).