Targeting pericyte-endothelial cell crosstalk by circular RNA-cPWWP2A inhibition aggravates diabetes-induced microvascular dysfunction
Targeting pericyte-endothelial cell crosstalk by circular RNA-cPWWP2A inhibition aggravates diabetes-induced microvascular dysfunction
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DOI：
10.1073/pnas.1814874116
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发表时间：
2019-04-09
影响因子：
11.1
通讯作者：
Yan, Biao
中科院分区：
文献类型：
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作者：
Liu, Chang;Ge, Hui-Min;Yan, Biao
血管周细胞和内皮细胞（EC）之间的串扰对于微血管稳定和重塑至关重要;然而，串扰通常被糖尿病破坏，导致严重甚至致命的血管损伤。环状RNA是一类内源性RNA，其调节多种重要的生理和病理过程。在这里，我们表明，糖尿病相关的压力上调cPWWP 2A的表达在周细胞，但不是在内皮细胞。体外研究表明，cPWWP 2A直接调节周细胞生物学，但通过携带cPWWP 2A的外泌体间接调节EC生物学。cPWWP 2A作为内源性miR-579海绵来隔离和抑制miR-579活性，导致血管生成素1、occludin和SIRT 1的表达增加。体内研究表明，cPWWP 2A过表达或miR-579抑制可加重糖尿病诱导的视网膜血管功能障碍。相比之下，通过沉默cPWWP 2A或过表达miR-579来抑制cPWWP 2A介导的信号传导会加剧视网膜血管功能障碍。总的来说，这项研究揭示了周细胞和EC沟通的机制。cPWWP 2A或miR-579表达的干预可能为治疗糖尿病微血管并发症提供机会。
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.