Thrombospondin-4 ablation reduces macrophage recruitment in adipose tissue and neointima and suppresses injury-induced restenosis in mice

Lei Lv; Wei Liang; Meng Ye; Jiwei Zhang; Hao Zhang; Guanhua Xue; Lan Zhang

doi:10.1016/j.atherosclerosis.2016.02.005

Thrombospondin-4 ablation reduces macrophage recruitment in adipose tissue and neointima and suppresses injury-induced restenosis in mice

Atherosclerosis. 2016 Apr:247:70-7. doi: 10.1016/j.atherosclerosis.2016.02.005. Epub 2016 Feb 11.

Authors

Lei Lv¹, Wei Liang¹, Meng Ye¹, Jiwei Zhang¹, Hao Zhang¹, Guanhua Xue², Lan Zhang³

Affiliations

¹ Department of Vascular Surgery, Ren ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
² Department of Vascular Surgery, Ren ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Electronic address: pudongnanlu@sohu.com.
³ Department of Vascular Surgery, Ren ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Electronic address: rjzhanglan@sjtu.edu.cn.

PMID: 26868511
DOI: 10.1016/j.atherosclerosis.2016.02.005

Abstract

Objective: Thrombospondin-4 (Thbs4) is a member of the extracellular calcium-binding protein family and is linked to cell adhesion and migration. Given the involvement of Thbs4 in vascular inflammation, we hypothesized that Thbs4 plays a role in restenosis.

Methods and results: Here we show evidence that Thbs4 is upregulated in wire-injured mouse arteries and correlated with CD68 expression. Macrophage infiltration is reduced in both adipose tissue (AT) and neointima of Thbs4/ApoE double knockout (DKO) mice after injury. Moreover, Thbs4 deficiency prevents restenosis in ApoE KO mice fed a Western-type diet (WTD). Lethally irradiated DKO mice that receive bone marrow from ApoE KO or DKO mice have reduced neointima development. While considering related mechanisms, we note decreased chemokine production in both AT and neointima of DKO mice. In addition, vascular smooth muscle cells (VSMCs) derived from DKO mice display suppressed proliferation and migration in comparison with controls. Thioglycollate (TG)-induced macrophages from DKO mice show retarded adhesion to VSMCs. Recombinant Thbs4 promoted macrophage adhesion to VSMCs, and enhanced VSMC proliferation and migration.

Conclusion: Collectively, these data highlight the significance of Thbs4 in regulating macrophage accumulation and treating restenosis.

Keywords: Adipose tissue; Macrophage; Restenosis; Thrombospondin-4.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adipose Tissue / metabolism*
Adipose Tissue / pathology
Animals
Apolipoproteins E / deficiency
Apolipoproteins E / genetics
Arterial Occlusive Diseases / genetics
Arterial Occlusive Diseases / metabolism
Arterial Occlusive Diseases / pathology
Arterial Occlusive Diseases / prevention & control*
Cell Adhesion
Cell Movement
Cell Proliferation
Cells, Cultured
Chemotaxis*
Constriction, Pathologic
Disease Models, Animal
Femoral Artery / injuries
Femoral Artery / metabolism*
Femoral Artery / pathology
Genetic Predisposition to Disease
Macrophages, Peritoneal / metabolism*
Macrophages, Peritoneal / pathology
Mice, Inbred C57BL
Mice, Knockout
Muscle, Smooth, Vascular / metabolism
Muscle, Smooth, Vascular / pathology
Myocytes, Smooth Muscle / metabolism
Myocytes, Smooth Muscle / pathology
Neointima*
Phenotype
Recurrence
Thrombospondins / deficiency*
Thrombospondins / genetics
Time Factors
Vascular Remodeling
Vascular System Injuries / genetics
Vascular System Injuries / metabolism*
Vascular System Injuries / pathology

Substances

Apolipoproteins E
Thrombospondins
thrombospondin 4