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Matrix Stiffening Induce Endothelial Dysfunction Via the TRPV4/MicroRNA-6740/ET-1 Mechanotransduction Pathway

29 Pages Posted: 19 May 2019 First Look: Under Review

See all articles by Xiang Song

Xiang Song

Academy of Military Medical Sciences - Institute of Health Service and Transfusion Medicine

Gan Chen

Academy of Military Medical Sciences - Institute of Health Service and Transfusion Medicine

Zhenwei Sun

People's Liberation Army (PLA), 988th Hospital, Department of Blood Transfusion

Pan Shang

Academy of Military Medical Sciences - Institute of Health Service and Transfusion Medicine

Guoxing You

Academy of Military Medical Sciences - Institute of Health Service and Transfusion Medicine

Jingxiang Zhao

Academy of Military Medical Sciences - Institute of Health Service and Transfusion Medicine

Sisi Liu

Tsinghua University - Department of Engineering Mechanics

Dong Han

Chinese Academy of Sciences (CAS) - National Centre for Nanoscience and Technology (NCNST)

Hong Zhou

Academy of Military Medical Sciences - Institute of Health Service and Transfusion Medicine

Abstract

Vascular stiffening is associated with the prognosis of cardiovascular disease (CVD). Endothelial dysfunction, as shown by reduced vasodilation and increased vasoconstriction,not only affects vascular tone, but also accelerates progression of CVD. However, the precise effect of vascular stiffening on endothelial function and its mechanism are still unclear. In this study, we found that increasing substrate stiffness promoted endothelin-1 (ET-1) expression and inhibited endothelial nitric oxide synthase expression in human umbilical vein endothelial cells. Additionally, miR-6740-5p was identified as a stiffness-sensitive microRNA, which was down regulated by a stiff substrate, and subsequently resulted in increased ET-1 expression.Furthermore, we found that substrate stiffening reduced expression and activity of the calcium channel TRPV4, which subsequently enhanced ET-1 expression by inhibiting miR-6740-5p. Finally, analysis of clinical plasma samples showed that plasma miR-6740-5p levels inpatients with carotid atherosclerosis were significantly lower than those in healthy people.Taken together, our findings show a novel mechanically regulated TRPV4/miR-6740/ET-1signaling axis by which substrate stiffness affects endothelial function. Our findings suggest that vascular stiffening induces endothelial dysfunction, and thereby accelerates progression of CVD. Furthermore, this study indicated that endothelial dysfunction induced by improper biophysical cues of cardiovascular implants may be an important reason for occurrence of complications for cardiovascular implants.

Keywords: Stiffness, Cardiovascular Disease, Endothelin-1, miR-6740-5p, TRPV4

Suggested Citation

Song, Xiang and Chen, Gan and Sun, Zhenwei and Shang, Pan and You, Guoxing and Zhao, Jingxiang and Liu, Sisi and Han, Dong and Zhou, Hong, Matrix Stiffening Induce Endothelial Dysfunction Via the TRPV4/MicroRNA-6740/ET-1 Mechanotransduction Pathway (May 14, 2019). Available at SSRN: https://ssrn.com/abstract=3387690

Xiang Song

Academy of Military Medical Sciences - Institute of Health Service and Transfusion Medicine

No. 27 Taiping Road
Beijing, 100850
China

Gan Chen (Contact Author)

Academy of Military Medical Sciences - Institute of Health Service and Transfusion Medicine ( email )

No. 27 Taiping Road
Beijing, 100850
China

Zhenwei Sun

People's Liberation Army (PLA), 988th Hospital, Department of Blood Transfusion

Zhengzhou, 450042
China

Pan Shang

Academy of Military Medical Sciences - Institute of Health Service and Transfusion Medicine

No. 27 Taiping Road
Beijing, 100850
China

Guoxing You

Academy of Military Medical Sciences - Institute of Health Service and Transfusion Medicine

No. 27 Taiping Road
Beijing, 100850
China

Jingxiang Zhao

Academy of Military Medical Sciences - Institute of Health Service and Transfusion Medicine

No. 27 Taiping Road
Beijing, 100850
China

Sisi Liu

Tsinghua University - Department of Engineering Mechanics

Beijing, 100084
China

Dong Han

Chinese Academy of Sciences (CAS) - National Centre for Nanoscience and Technology (NCNST) ( email )

No.11 ZhongGuanCun BeiYiTiao
Beijing, 100190
China

Hong Zhou

Academy of Military Medical Sciences - Institute of Health Service and Transfusion Medicine ( email )

No. 27 Taiping Road
Beijing, 100850
China

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