Vascular Semaphorin 7A Upregulation by Disturbed Flow Promotes Atherosclerosis Through Endothelial beta 1 Integrin

• Type of Material: Article
• Authors: Shuhong Hu, Soochow University; Yifei Liu, Soochow University; Tao You, Soochow University; Jack Heath, Georgia Institute of Technology; Linru Xu, Soochow University; Xiaowei Zheng, Soochow University; Aili Wang, Soochow University; Yinyan Wang, Soochow University; Fengchan Li, Soochow University; Fei Yang, Soochow University; Yiren Cao, Soochow University; Huayu Zhang, Leiden University; Janine M. van Gils, Leiden University; Anton Jan van Zonneveld, Leiden University; Hanjoong Jo, Emory University; Qingyu Wu, Soochow University; Yonghong Zhang, Soochow University; Chaojun Tang, Soochow University; Li Zhu, Soochow University
• Language: English
• Date: 2018-02-01
• Publisher: American Heart Association
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 American Heart Association, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1161/ATVBAHA.117.310491
• Title of Journal or Parent Work: Arteriosclerosis, Thrombosis, and Vascular Biology
• ISSN: 1079-5642
• Volume: 38
• Issue: 2
• Start Page: 335
• End Page: 343
• Grant/Funding Information: This work was supported in part by grants from the Natural Science Foundation of China (81620108001, 81370373, and 91439112 to L.Z. and 31300781 and 81670134 to C.T.), the Netherlands Heart Foundation (2013T127 to H.Z. and J.M.G.), the National Institutes of Health (HL119798 and HL095070 to HJ) and the Priority Academic Program Development of Jiangsu Higher Education Institutions of China.
• Keywords: IN-VIVO; Life Sciences & Biomedicine; HEMODYNAMIC SHEAR-STRESS; Science & Technology; diet, high fat; Cardiovascular System & Cardiology; semaphorins; ACUTE LUNG INJURY; RECEPTORS; MECHANOSENSITIVE GENES; Hematology; monocytes; EXPRESSION; INFLAMMATION; atherosclerosis; Peripheral Vascular Disease; upregulation; FACTOR-KAPPA-B; CELLS; GUIDANCE
• Research Categories: Health Sciences, Epidemiology; Engineering, Biomedical; Health Sciences, Public Health

Abstract

Objective-Accumulating evidence suggests a role of semaphorins in vascular homeostasis. Here, we investigate the role of Sema7A (semaphorin 7A) in atherosclerosis and its underlying mechanism. Approach and Results-Using genetically engineered Sema7A -/- ApoE -/- mice, we showed that deletion of Sema7A attenuates atherosclerotic plaque formation primarily in the aorta of ApoE -/- mice on a high-fat diet. A higher level of Sema7A in the atheroprone lesser curvature suggests a correlation of Sema7A with disturbed flow. This notion is supported by elevated Sema7A expression in human umbilical venous endothelial cells either subjected to oscillatory shear stress or treated with the PKA (protein kinase A)/CREB (cAMP response element-binding protein) inhibitor H89 (N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide·2HCl hydrate). Further studies using the partial carotid artery ligation model showed that disturbed flow in the left carotid artery of Sema7A +/+ ApoE -/- mice promoted the expression of endothelial Sema7A and cell adhesion molecules, leukocyte adhesion, and plaque formation, whereas such changes were attenuated in Sema7A -/- ApoE -/- mice. Further studies showed that blockage of β1 integrin, a known Sema7A receptor, or inhibition of FAK (focal adhesion kinase), MEK1/2 (mitogen-Activated protein kinase kinase 1/2), or NF-κB (nuclear factor-κB) significantly reduced the expression of cell adhesion molecules and THP-1 (human acute monocytic leukemia cell line) monocyte adhesion in Sema7A-overexpressing human umbilical venous endothelial cells. Studies using chimeric mice suggest that vascular, most likely endothelial, Sema7A plays a major role in atherogenesis. Conclusions-Our findings indicate a significant role of Sema7A in atherosclerosis by mediating endothelial dysfunction in a β1 integrin-dependent manner.