Metabolic control of smooth muscle cell phenotype switching in atherosclerosis.
RM, Z., X, Z., H, B., J, Z., Y, L., PY, C., YH, S., G, T., N, S., & C, J. (2026). Metabolic control of smooth muscle cell phenotype switching in atherosclerosis.. Science advances. https://doi.org/10.1126/sciadv.aef6065
RM Z, X Z, H B, J Z, Y L, PY C, et al. Metabolic control of smooth muscle cell phenotype switching in atherosclerosis.. Science advances. 2026; doi: 10.1126/sciadv.aef6065
RM Z, X Z, H B, et al. Metabolic control of smooth muscle cell phenotype switching in atherosclerosis.[J]. Science advances. 2026. DOI: 10.1126/sciadv.aef6065.
@article{rm2026,
author = {Zhang RM and Zhu X and Bae H and Zhang J and Li Y and Chen PY and Shen YH and Tellides G and Snyder N and Jang C},
title = {Metabolic control of smooth muscle cell phenotype switching in atherosclerosis.},
journal = {Science advances},
year = {2026},
doi = {10.1126/sciadv.aef6065},
note = {PMID: 42647644},
}
TY - JOUR AU - Zhang RM AU - Zhu X AU - Bae H AU - Zhang J AU - Li Y AU - Chen PY AU - Shen YH AU - Tellides G AU - Snyder N AU - Jang C TI - Metabolic control of smooth muscle cell phenotype switching in atherosclerosis. T2 - Science advances PY - 2026 DO - 10.1126/sciadv.aef6065 AN - PMID:42647644 ER -
The loss of smooth muscle cell (SMC) contractile phenotype contributes to various diseases including atherosclerosis. However, its metabolic basis is not entirely elucidated. Since the transforming growth factor beta (TGFβ) signaling is among principal regulators of SMC contractility, we studied metabolic regulation of TGFβ signaling in SMCs in vitro and atherosclerotic mouse models and human lesions. We found that TGFβ induced Ac-CoA synthetase 2 (ACSS2)-dependent Ac-CoA production, by suppressing pyruvate dehydrogenase kinase 4 (PDK4). This stabilized R-SMADs and TGFβ receptor 1, preserving SMC contractile phenotype. SMC-specific PDK4 knockout mimicked the effect of TGFβ signaling both metabolically and phenotypically, increasing glucose-derived synthesis of Ac-CoA and SMC contractile phenotype. SMC-specific Pdk4 knockout in ApoE knockout mice reduced atherosclerosis. Furthermore, human specimens demonstrated a strong correlation between PDK4 level and atherosclerosis severity. These findings indicate that continuous SMC TGFβ signaling, critical to the maintenance of the normal SMC contractile state, is regulated by PDK4 and carbohydrate metabolism.