mTOR signalling controls the formation of smooth muscle cell-derived luminal myofibroblasts during vasculitis

Stock, AT; Parsons, S; Hansen, JA; D&#39;Silva, DB; Starkey, G; Fayed, A; Lim, XY; D&#39;Costa, R; Gordon, CL; Wicks, IP

Author(s): Stock, AT; Parsons, S; Hansen, JA; D'Silva, DB; Starkey, G; Fayed, A; Lim, XY; D'Costa, R; Gordon, CL; Wicks, IP;
Details: Publication Year 2024-09-13,Volume 25,Issue #10,Page 4570-4593
Journal Title: EMBO Reports
Abstract: The accumulation of myofibroblasts within the intimal layer of inflamed blood vessels is a potentially catastrophic complication of vasculitis, which can lead to arterial stenosis and ischaemia. In this study, we have investigated how these luminal myofibroblasts develop during Kawasaki disease (KD), a paediatric vasculitis typically involving the coronary arteries. By performing lineage tracing studies in a murine model of KD, we reveal that luminal myofibroblasts develop independently of adventitial fibroblasts and endothelial cells, and instead derive from smooth muscle cells (SMCs). Notably, the emergence of SMC-derived luminal myofibroblasts-in both mice and patients with KD, Takayasu's arteritis and Giant Cell arteritis-coincided with activation of the mechanistic target of rapamycin (mTOR) signalling pathway. Moreover, SMC-specific deletion of mTOR signalling, or pharmacological inhibition, abrogated the emergence of luminal myofibroblasts. Thus, mTOR is an intrinsic and essential regulator of luminal myofibroblast formation that is activated in vasculitis patients and therapeutically tractable. These findings provide molecular insight into the pathogenesis of coronary artery stenosis and identify mTOR as a therapeutic target in vasculitis.
Publisher: Portland Press
Keywords: Kawasaki Disease; Myofibroblasts; Stenosis; Vasculitis; mTOR
Research Division(s): Inflammation; Blood Cells and Blood Cancer
PubMed ID: 39271773
Publisher's Version: https://doi.org/10.1038/s44319-024-00251-1
Open Access at Publisher's Site: https://doi.org/10.1038/s44319-024-00251-1
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-10-04 10:45:15

Last Modified: 2024-10-25 10:50:51