Injury to the tunica media initiates atherogenesis in the presence of hyperlipidemia

Hanane Belhoul-Fakir; Jiansha Wu; Yen L Yeow; Gabrielle C Musk; Helen Kershaw; Evan Ingley; Bichen Sophie Zhao; Christopher M Reid; Christopher Lagat; Brian Evans; Peter L Thompson; Michael L Brown; Juliana Hamzah; Shirley Jansen

doi:10.3389/fcvm.2023.1152124

Injury to the tunica media initiates atherogenesis in the presence of hyperlipidemia

Front Cardiovasc Med. 2023 Mar 30:10:1152124. doi: 10.3389/fcvm.2023.1152124. eCollection 2023.

Authors

Hanane Belhoul-Fakir^{1

2

3}, Jiansha Wu^{2

3}, Yen L Yeow², Gabrielle C Musk⁴, Helen Kershaw⁴, Evan Ingley^{5

6

7}, Bichen Sophie Zhao^{1

2}, Christopher M Reid^{8

9}, Christopher Lagat¹⁰, Brian Evans¹⁰, Peter L Thompson^{2

3}, Michael L Brown⁹, Juliana Hamzah^{1

2

3}, Shirley Jansen^{1

2

3

11}

Affiliations

¹ Curtin Medical School, Curtin University, Bentley, Perth, WA, Australia.
² Laboratory of Targeted Drug Delivery, Imaging & Therapy, Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, WA, Australia.
³ Heart & Vascular Research Institute, Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, WA, Australia.
⁴ Animal Care Services, The University of Western Australia, Crawley, Perth, WA, Australia.
⁵ Discipline of Medical, Molecular, and Forensic Sciences, Murdoch University, Murdoch, WA, Australia.
⁶ School of Biomedical Sciences, Pharmacology, and Toxicology, The University of Western Australia, Perth, WA, Australia.
⁷ Centre for Medical Research, The University of Western Australia, Perth, WA, Australia.
⁸ School of Public Health and Preventive Medicine, Monash University, Clayton, VIC, Australia.
⁹ School of Population Health, Curtin University, Bentley, Perth, WA, Australia.
¹⁰ Western Australia School of Mine: Minerals, Energy and Chemical Engineering, Curtin University, Kensington, Perth, WA, Australia.
¹¹ Department of Vascular and Endovascular Surgery, Sir Charles Gairdner Hospital, Nedlands, Perth, WA, Australia.

Abstract

Background and aims: Fatty streaks initiating the formation of atheromatous plaque appear in the tunica intima. The tunica media is not known to be a nidus for lipid accumulation initiating atherogenesis. We assessed changes to the tunica media in response to a micro-injury produced in the pig aorta. In addition, we assessed human carotid endarterectomy plaques for indication of atheroma initiation in the tunica media.

Methods: Three healthy landrace female pigs underwent laparotomy to inject autologous blood and create micro-hematomas at 6 sites within the tunica media of the infrarenal abdominal aorta. These pigs were fed a high-fat diet (HFD) for 4-12 weeks. Post-mortem aortas from all pigs, including a control group of healthy pigs, were serially stained to detect lipid deposits, vasa vasora (VV), immune cell infiltration and inflammatory markers, as well as changes to the vascular smooth muscle cell (vSMC) compartment. Moreover, 25 human carotid endarterectomy (CEA) specimens were evaluated for their lipid composition in the tunica media and intima.

Results: High lipid clusters, VV density, and immune cell infiltrates were consistently observed at 5 out of 6 injection sites under prolonged hyperlipidemia. The hyperlipidemic diet also affected the vSMC compartment in the tunica media adjacent to the tunica adventitia, which correlated with VV invasion and immune cell infiltration. Analysis of human carotid specimens post-CEA indicated that 32% of patients had significantly greater atheroma in the tunica media than in the arterial intima.

Conclusion: The arterial intima is not the only site for atherosclerosis initiation. We show that injury to the media can trigger atherogenesis.

Keywords: Vasa vasora; atherogenesis; atheroma; atherosclerosis; inflammation; tunica media; vascular smooth muscle cell; wall stress.

Grants and funding

This work was supported by WA Vascular Research Fund, Harry Perkins Medical Research Institute and the Miles Family.