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Proc Natl Acad Sci U S A. 2019 Apr 9;116(15):7455-7464. doi: 10.1073/pnas.1814874116. Epub 2019 Mar 26.

Targeting pericyte-endothelial cell crosstalk by circular RNA-cPWWP2A inhibition aggravates diabetes-induced microvascular dysfunction.

Liu C1,2,3, Ge HM2,3, Liu BH4, Dong R4, Shan K1, Chen X5, Yao MD2,3, Li XM2, Yao J2,3, Zhou RM1, Zhang SJ1, Jiang Q6,3, Zhao C7,8,9,10, Yan B7,8,9,10.

Author information

1
Eye Institute, Eye and ENT Hospital, Shanghai Medical College, Fudan University, Shanghai 200031, China.
2
The Affiliated Eye Hospital, Nanjing Medical University, Nanjing 210029, China.
3
The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing 210029, China.
4
Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai 201102, China.
5
Department of Ophthalmology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
6
The Affiliated Eye Hospital, Nanjing Medical University, Nanjing 210029, China; yanbiao1982@hotmail.com dr_zhaochen@163.com jqin710@vip.sina.com.
7
Eye Institute, Eye and ENT Hospital, Shanghai Medical College, Fudan University, Shanghai 200031, China; yanbiao1982@hotmail.com dr_zhaochen@163.com jqin710@vip.sina.com.
8
National Health Commission (NHC) Key Laboratory of Myopia, Fudan University, Shanghai 200031, China.
9
Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai 200031, China.
10
Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai 200031, China.

Abstract

The crosstalk between vascular pericytes and endothelial cells (ECs) is critical for microvascular stabilization and remodeling; however, the crosstalk is often disrupted by diabetes, leading to severe and even lethal vascular damage. Circular RNAs are a class of endogenous RNAs that regulate several important physiological and pathological processes. Here we show that diabetes-related stress up-regulates cPWWP2A expression in pericytes but not in ECs. In vitro studies show that cPWWP2A directly regulates pericyte biology but indirectly regulates EC biology via exosomes carrying cPWWP2A. cPWWP2A acts as an endogenous miR-579 sponge to sequester and inhibit miR-579 activity, leading to increased expression of angiopoietin 1, occludin, and SIRT1. In vivo studies show that cPWWP2A overexpression or miR-579 inhibition alleviates diabetes mellitus-induced retinal vascular dysfunction. By contrast, inhibition of cPWWP2A-mediated signaling by silencing cPWWP2A or overexpressing miR-579 aggravates retinal vascular dysfunction. Collectively, this study unveils a mechanism by which pericytes and ECs communicate. Intervention of cPWWP2A or miR-579 expression may offer opportunities for treating diabetic microvascular complications.

KEYWORDS:

circular RNA; endothelial cell; microRNA sponge; pericyte; retinal vascular dysfunction

PMID:
30914462
PMCID:
PMC6462073
[Available on 2019-09-26]
DOI:
10.1073/pnas.1814874116
[Indexed for MEDLINE]

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