Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 42, Issue 8, Pages 1005-1022Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.121.317451
Keywords
diet; high-fat; hypercholesterolemia; muscle; smooth; vascular; plaque; atherosclerotic
Categories
Funding
- National Heart, Lung and Blood Institute [RO1 HL146583]
- American Heart Association Merit Award
- Marfan Foundation McKusick Fellowship Award
- NIH [S10OD023469, S10OD025240, P30EY002520, T32GM120011, RO1DK114356, UM1HG006348]
- American Heart Association [20CDA35310689]
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This study reveals that hypercholesterolemia drives complex phenotypic modulation of vascular smooth muscle cells (SMCs) and leads to atherosclerotic plaque formation. Deficiency of Perk in SMCs reduces plaque formation and prevents migration of SMCs from the medial layer of the aorta.
Background: Vascular smooth muscle cells (SMCs) undergo complex phenotypic modulation with atherosclerotic plaque formation in hyperlipidemic mice, which is characterized by de-differentiation and heterogeneous increases in the expression of macrophage, fibroblast, osteogenic, and stem cell markers. An increase of cellular cholesterol in SMCs triggers similar phenotypic changes in vitro with exposure to free cholesterol due to cholesterol entering the endoplasmic reticulum, triggering endoplasmic reticulum stress and activating Perk (protein kinase RNA-like endoplasmic reticulum kinase) signaling. Methods: We generated an SMC-specific Perk knockout mouse model, induced hyperlipidemia in the mice by AAV-PCSK9(DY) injection, and subjected them to a high-fat diet. We then assessed atherosclerotic plaque formation and performed single-cell transcriptomic studies using aortic tissue from these mice. Results: SMC-specific deletion of Perk reduces atherosclerotic plaque formation in male hyperlipidemic mice by 80%. Single-cell transcriptomic data identify 2 clusters of modulated SMCs in hyperlipidemic mice, one of which is absent when Perk is deleted in SMCs. The 2 modulated SMC clusters have significant overlap of transcriptional changes, but the Perk-dependent cluster uniquely shows a global decrease in the number of transcripts. SMC-specific Perk deletion also prevents migration of both contractile and modulated SMCs from the medial layer of the aorta. Conclusions: Our results indicate that hypercholesterolemia drives both Perk-dependent and Perk-independent SMC modulation and that deficiency of Perk significantly blocks atherosclerotic plaque formation.
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