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Exosomes Derived from HeLa Cells Break Down Vascular Integrity by Triggering Endoplasmic Reticulum Stress in Endothelial Cells

49 Pages Posted: 16 Apr 2019

See all articles by Yinuo Lin

Yinuo Lin

Wenzhou Medical University - Wenzhou Municipal Key Cardiovascular Research Laboratory; Zhejiang University - Department of Cardiology

Chi Zhang

Zhejiang University - Department of Cardiology

Pingping Xiang

Zhejiang University - Provincial Key Cardiovascular Research Laboratory

Jian Shen

Zhejiang University - Provincial Key Cardiovascular Research Laboratory; Zhejiang University - Department of Cardiology

Hong Yu

Zhejiang University - Department of Cardiology; Zhejiang University - Provincial Key Cardiovascular Research Laboratory

More...

Abstract

Background: During tumorigenesis, exosomes have been demonstrated to promote tumor angiogenesis and metastasis. Here we explored the effect of HeLa cell-derived exosomes (ExoHela) on endothelial tight junctions (TJ) and the related mechanisms.

Methods: Primary human umbilical vein endothelial cells (HUVECs) were treated with HeLa cell-derived exosomes (ExoHela) or human cervical epithelial cell-derived exosomes (ExoHCEC). The permeability of endothelial monolayer, expression levels of zonula occludens-1 (ZO-1) and Claudin-5, as well as profiles of exosomal microRNAs and ExoHela-treated HUVECs mRNAs were analyzed. Effects of ExoHela on vascular permeability and tumor metastasis in vivo were also evaluated.

Findings: After mixing HUVEC with ExoHela, ZO-1 and Claudin-5 levels in HUVEC were significantly reduced, and the permeability of endothelial monolayer was increased while mRNA levels of ZO-1 and Claudin-5 remained unchanged. Injection of ExoHela into mice increased vascular permeability and tumor metastasis in vivo. Neither knocking down of Dicer nor use of inhibitors of microRNAs targeting at mRNAs of ZO-1 and Claudin-5 could block the inhibitory effect ofExoHela on ZO-1 and Claudin-5. It was found that expression of genes involved in endoplasmic reticulum (ER) stress was significantly increased in HUVECs after treated with ExoHela. Inhibition of ER stress by knocking down PERK partially restored the protein level of ZO-1 and Claudin-5.

Interpretation: ExoHela break down endothelial integrity and promote tumor metastasis by triggering ER stress in ECs. Such effect is microRNA-independent.

Funding Statement: National Natural Science Foundation of China (81570251, 81528002), and Wenzhou Municipal Science and Technology Bureau Foundation (Y20170052).

Declaration of Interests: No potential conflicts of interest were disclosed by all authors.

Ethics Approval Statement: Normal human umbilical cords were obtained with written consent from healthy donors with the approval of the Human Subjects Ethics Committee of Second Affiliated Hospital of Zhejiang University.

The animal protocol was approved by Zhejiang University according to Chinese guidelines for laboratory animal care and use.

Keywords: Exosome; Tight junction; Endoplasmic reticulum stress; Vascular permeability; Metastasis

Suggested Citation

Lin, Yinuo and Zhang, Chi and Xiang, Pingping and Shen, Jian and Yu, Hong, Exosomes Derived from HeLa Cells Break Down Vascular Integrity by Triggering Endoplasmic Reticulum Stress in Endothelial Cells (April 15, 2019). Available at SSRN: https://ssrn.com/abstract=3372422 or http://dx.doi.org/10.2139/ssrn.3372422

Yinuo Lin

Wenzhou Medical University - Wenzhou Municipal Key Cardiovascular Research Laboratory ( email )

Wenzhou, Zhejiang
China

Zhejiang University - Department of Cardiology

China

Chi Zhang

Zhejiang University - Department of Cardiology

China

Pingping Xiang

Zhejiang University - Provincial Key Cardiovascular Research Laboratory

Zhejiang
China

Jian Shen

Zhejiang University - Provincial Key Cardiovascular Research Laboratory

Zhejiang
China

Zhejiang University - Department of Cardiology

China

Hong Yu (Contact Author)

Zhejiang University - Department of Cardiology ( email )

China

Zhejiang University - Provincial Key Cardiovascular Research Laboratory ( email )

Zhejiang
China

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