Endothelial Foxp1 Regulates Neointimal Hyperplasia Via Matrix Metalloproteinase‐9/Cyclin Dependent Kinase Inhibitor 1B Signal Pathway

Author:

Chen Xiaoli1,Xu Jianfei1,Bao Wenzhen1,Li Hongda1,Wu Wenrun1ORCID,Liu Jiwen1,Pi Jingjiang2,Tomlinson Brian3ORCID,Chan Paul4ORCID,Ruan Chengchao5ORCID,Zhang Qi2,Zhang Lin1,Fan Huimin1,Morrisey Edward6,Liu Zhongmin1,Zhang Yuzhen1,Lin Li2,Liu Jie1ORCID,Zhuang Tao157ORCID

Affiliation:

1. Key Laboratory of Arrhythmias of the Ministry of Education of China Research Center for Translational Medicine Shanghai East Hospital Tongji University School of Medicine Shanghai China

2. Department of Cardiology Shanghai East Hospital Tongji University School of Medicine Shanghai China

3. Faculty of Medicine Macau University of Science and Technology Macau China

4. Division of Cardiology Department of Internal Medicine Wan Fang Hospital Taipei Medical University Taipei Taiwan

5. Department of Physiology and Pathophysiology School of Basic Medical Sciences Fudan University Shanghai China

6. Department of Cell and Developmental Biology (R.W., E.E.M.) Department of Medicine (E.E.M.) Penn Cardiovascular Institute (E.E.M.), and Penn Institute for Regenerative Medicine (E.E.M.) University of Pennsylvania Philadelphia Pennsylvania

7. Shanghai Jinshan Eye Disease Prevention and Treatment Institute Shanghai Jinshan Nuclear and Chemical Injury Emergency Treatment Center Jinshan Hospital Fudan University Shanghai China

Abstract

Background The endothelium is essential for maintaining vascular physiological homeostasis and the endothelial injury leads to the neointimal hyperplasia because of the excessive proliferation of vascular smooth muscle cells. Endothelial Foxp1 (forkhead box P1) has been shown to control endothelial cell (EC) proliferation and migration in vitro. However, whether EC‐Foxp1 participates in neointimal formation in vivo is not clear. Our study aimed to investigate the roles and mechanisms of EC‐Foxp1 in neointimal hyperplasia. Methods and Results The wire injury femoral artery neointimal hyperplasia model was performed in Foxp1 EC‐specific loss‐of‐function and gain‐of‐function mice. EC‐Foxp1 deletion mice displayed the increased neointimal formation through elevation of vascular smooth muscle cell proliferation and migration, and the reduction of EC proliferation hence reendothelialization after injury. In contrast, EC‐Foxp1 overexpression inhibited the neointimal formation. EC‐Foxp1 paracrine regulated vascular smooth muscle cell proliferation and migration via targeting matrix metalloproteinase‐9. Also, EC‐Foxp1 deletion impaired EC repair through reduction of EC proliferation via increasing cyclin dependent kinase inhibitor 1B expression. Delivery of cyclin dependent kinase inhibitor 1B‐siRNA to ECs using RGD (Arg‐Gly‐Asp)‐peptide magnetic nanoparticle normalized the EC‐Foxp1 deletion‐mediated impaired EC repair and attenuated the neointimal formation. EC‐Foxp1 regulates matrix metalloproteinase‐9/cyclin dependent kinase inhibitor 1B signaling pathway to control injury induced neointimal formation. Conclusions Our study reveals that targeting EC‐Foxp1‐matrix metalloproteinase‐9/cyclin dependent kinase inhibitor 1B pathway might provide future novel therapeutic interventions for restenosis.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine

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