Plexin D1 mediates disturbed flow-induced M1 macrophage polarization in atherosclerosis

Suhui Zhang; Yingqian Zhang; Peng Zhang; Zechen Wei; Mingrui Ma; Wei Wang; Wei Tong; Feng Tian; Hui Hui; Jie Tian; Yundai Chen

doi:10.1016/j.heliyon.2023.e17314

Plexin D1 mediates disturbed flow-induced M1 macrophage polarization in atherosclerosis

Heliyon. 2023 Jun 14;9(6):e17314. doi: 10.1016/j.heliyon.2023.e17314. eCollection 2023 Jun.

Authors

Suhui Zhang^{1

2}, Yingqian Zhang², Peng Zhang³, Zechen Wei^{4

5}, Mingrui Ma^{1

2}, Wei Wang², Wei Tong², Feng Tian², Hui Hui^{4

5}, Jie Tian^{4

6

7}, Yundai Chen²

Affiliations

¹ Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing, 100853, China.
² Senior Department of Cardiology, The Sixth Medical Center of PLA General Hospital, Beijing, 100048, China.
³ School of Computer and Information Technology, Beijing Jiaotong University, Beijing, 100044, China.
⁴ CAS Key Laboratory of Molecular Imaging, Beijing Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China.
⁵ University of Chinese Academy of Sciences, Beijing, 100080, China.
⁶ Key Laboratory of Big Data-Based Precision Medicine (Beihang University), Ministry of Industry and Information Technology of China, Beijing, 100191, China.
⁷ Zhuhai Precision Medical Center, Zhuhai People's Hospital, Affiliated with Jinan University, Zhuhai, 519000, China.

Abstract

Atherosclerosis preferentially develops at bifurcations exposed to disturbed flow. Plexin D1 (PLXND1) responds to mechanical forces and drives macrophage accumulation in atherosclerosis. Here, multiple strategies were used to identify the role of PLXND1 in site-specific atherosclerosis. Using computational fluid dynamics and three-dimensional light-sheet fluorescence-microscopy, the elevated PLXND1 in M1 macrophages was mainly distributed in disturbed flow area of ApoE^-/- carotid bifurcation lesions, and visualization of atherosclerosis in vivo was achieved by targeting PLXND1. Subsequently, to simulate the microenvironment of bifurcation lesions in vitro, we co-cultured oxidized low-density lipoprotein (oxLDL)-treated THP-1-derived macrophages with shear-treated human umbilical vein endothelial cells (HUVECs). We found that oscillatory shear induced the increase of PLXND1 in M1 macrophages, and knocking down PLXND1 inhibited M1 polarization. Semaphorin 3E, the ligand of PLXND1 which was highly expressed in plaques, strongly enhanced M1 macrophage polarization via PLXND1 in vitro. Our findings provide insights into pathogenesis in site-specific atherosclerosis that PLXND1 mediates disturbed flow-induced M1 macrophage polarization.

Keywords: Atherosclerosis; Bifurcation lesions; Disturbed flow; Macrophage polarization; Plexin D1.