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Sci Rep. 2017 May 31;7(1):2528. doi: 10.1038/s41598-017-02852-4.

A PPARγ-dependent miR-424/503-CD40 axis regulates inflammation mediated angiogenesis.

Author information

1
Department of Life Systems, Sookmyung Women's University, 52 Hyochangwon-gil, Yongsan-gu, Seoul, 140-742, Korea.
2
Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT, USA.
3
Department of Life Systems, Sookmyung Women's University, 52 Hyochangwon-gil, Yongsan-gu, Seoul, 140-742, Korea. jkim@sookmyung.ac.kr.
4
Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT, USA. jkim@sookmyung.ac.kr.
5
Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT, USA. hyung.chun@yale.edu.

Abstract

Activation of the endothelium by pro-inflammatory stimuli plays a key role in the pathogenesis of a multitude of vascular diseases. Angiogenesis is a crucial component of the vascular response associated with inflammatory signaling. The CD40/CD40 ligand dyad in endothelial cells (EC) has a central role in promoting vascular inflammatory response; however, the molecular mechanism underlying this component of inflammation and angiogenesis is not fully understood. Here we report a novel microRNA mediated suppression of endothelial CD40 expression. We found that CD40 is closely regulated by miR-424 and miR-503, which directly target its 3' untranslated region. Pro-inflammatory stimuli led to increased endothelial CD40 expression, at least in part due to decreased miR-424 and miR-503 expression. In addition, miR-424 and miR-503 reduced LPS induced EC sprouting, migration and tube formation. Moreover, we found that miR-424 and miR-503 expression is directly regulated by peroxisome proliferator-activated receptor gamma (PPARγ), whose endothelial expression and activity are decreased in response to inflammatory factors. Finally, we demonstrate that mice with endothelial-specific deletion of miR-322 (miR-424 ortholog) and miR-503 have augmented angiogenic response to LPS in a Matrigel plug assay. Overall, these studies identify a PPARγ-dependent miR-424/503-CD40 signaling axis that is critical for regulation of inflammation mediated angiogenesis.

PMID:
28566713
PMCID:
PMC5451412
DOI:
10.1038/s41598-017-02852-4
[Indexed for MEDLINE]
Free PMC Article

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