Deletion of Yes‐Associated Protein in Vascular Smooth Muscle Cells Alleviates Atherosclerosis

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 ΔVSMC ApoE −/− 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.