Elevated Expression of miR302-367 in Endothelial Cells Inhibits Developmental Angiogenesis via CDC42/CCND1 Mediated Signaling Pathways

Elevated Expression of miR302-367 in Endothelial Cells Inhibits Developmental Angiogenesis via CDC42/CCND1 Mediated Signaling Pathways.

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.7150/thno.21986
Journal or Publication Title: Theranostics
Volume: 8
Number: 6
Page Range: pp. 1511-1526
Date: 2018
Divisions: Cell Signalling
Depositing User: General Admin
Identification Number: 10.7150/thno.21986
ISSN: 1838-7640
Date Deposited: 04 Jan 2021 23:16
Abstract:

Rationale: Angiogenesis is critical for embryonic development and microRNAs fine-tune this process, but the underlying mechanisms remain incompletely understood.

Methods: Endothelial cell (EC) specific miR302-367 line was used as gain-of-function and anti-miRs as loss-of-function models to investigate the effects of miR302-367 on developmental angiogenesis with embryonic hindbrain vasculature as an in vivo model and fibrin gel beads and tube formation assay as in vitro models. Cell migration was evaluated by Boyden chamber and scratch wound healing assay and cell proliferation by cell count, MTT assay, Ki67 immunostaining and PI cell cycle analysis. RNA high-throughput sequencing identified miR-target genes confirmed by chromatin immunoprecipitation and 3'-UTR luciferase reporter assay, and finally target site blocker determined the pathway contributing significantly to the phenotype observed upon microRNA expression.

Results: Elevated EC miR302-367 expression reduced developmental angiogenesis, whereas it was enhanced by inhibition of miR302-367, possibly due to the intrinsic inhibitory effects on EC migration and proliferation. We identified Cdc42 as a direct target gene and elevated EC miR302-367 decreased total and active Cdc42, and further inhibited F-actin formation via the WASP and Klf2/Grb2/Pak1/LIM-kinase/Cofilin pathways. MiR302-367-mediated-Klf2 regulation of Grb2 for fine-tuning Pak1 activation contributing to the inhibited F-actin formation, and then the attenuation of EC migration. Moreover, miR302-367 directly down-regulated EC Ccnd1 and impaired cell proliferation via the Rb/E2F pathway.

Conclusion: miR302-367 regulation of endothelial Cdc42 and Ccnd1 signal pathways for EC migration and proliferation advances our understanding of developmental angiogenesis, and meanwhile provides a rationale for future interventions of pathological angiogenesis that shares many common features of physiological angiogenesis.

Keywords: miR302-367, endothelial cells, developmental angiogenesis, cdc42, actin remodeling, cell cycle.

Creators:
Creators
Email
Pi, Jingjiang
UNSPECIFIED
Liu, Jie
UNSPECIFIED
Zhuang, Tao
UNSPECIFIED
Zhang, Lin
UNSPECIFIED
Sun, Huimin
UNSPECIFIED
Chen, Xiaoli
UNSPECIFIED
Zhao, Qian
UNSPECIFIED
Kuang, Yashu
UNSPECIFIED
Peng, Sheng
UNSPECIFIED
Zhou, Xiaohui
UNSPECIFIED
Yu, Zuoren
UNSPECIFIED
Tao, Ting
UNSPECIFIED
Tomlinson, Brian
UNSPECIFIED
Chan, Paul
UNSPECIFIED
Tian, Ying
UNSPECIFIED
Fan, Huimin
UNSPECIFIED
Liu, Zhongmin
UNSPECIFIED
Zheng, Xiangjian
UNSPECIFIED
Morrisey, Edward
UNSPECIFIED
Zhang, Yuzhen
UNSPECIFIED
Last Modified: 04 Jan 2021 23:16
URI: https://eprints.centenary.org.au/id/eprint/581

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