J Am Heart Assoc. 2026 Nov 12:e042381. doi: 10.1161/JAHA.125.042381. Online ahead of print.

ABSTRACT

BACKGROUND: The migration and proliferation of vascular smooth muscle cells (VSMCs) are critical processes in the development of atherosclerosis. YAP (Yes-associated protein) regulates VSMC migration and proliferation. However, its specific role in atherosclerosis remains unclear.

METHODS: Atherosclerosis models were generated in mice injected with adeno-associated virus 8-mPCSK9 (murine proprotein convertase subtilisin/kexin type 9) or ApoE^-/- (apolipoprotein E knockout) mice by being fed a high-cholesterol diet. Primary VSMCs were used to elucidate its mechanism.

RESULTS: YAP expression was elevated in VSMCs within mouse atherosclerotic plaques. Both tamoxifen-mediated YAP^ΔVSMC or adeno-associated virus-inducible VSMC-specific YAP knockout mice injected with adeno-associated virus 8-mPCSK9 and YAP^ΔVSMCApoE^-/- mice exhibited alleviated atherosclerotic phenotype. Further study found that angiopoietin-2 overexpression induced VSMC phenotypic switching, migration, and proliferation in YAP knockout VSMCs stimulated with platelet-derived growth factor-BB in vitro. Furthermore, the VSMC-specific angiopoietin-2 overexpression could completely reverse VSMC YAP deficiency-alleviated atherosclerotic phenotype and the effect of YAP-mediated VSMC phenotypic switching. Mechanistically, YAP upregulated angiopoietin-2 via TEAD4 (murine TEA domain family member 4) in VSMCs.

CONCLUSIONS: In conclusion, our findings revealed that YAP promotes atherosclerosis by inducing angiopoietin-2-mediated VSMC phenotypic switching via TEAD4. Inhibition of VSMC YAP may be an effective therapeutic strategy for atherosclerosis.

PMID:43018070 | DOI:10.1161/JAHA.125.042381