mTOR signaling controls the formation of smooth muscle cell-derived intimal fibroblasts during vasculitis

Abstract

The excessive accumulation of fibroblasts within the intimal layer of inflamed vessels is a feared complication of vasculitis, which can lead to arterial stenosis and ischemia. In this study, we have investigated how such intimal fibroblasts 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 vasculitis-induced intimal fibroblasts develop independently of both adventitial fibroblasts and endothelial cells, and instead derive from smooth muscle cells (SMCs). Notably, the emergence of SMC-derived intimal fibroblasts - in both mice and in patients with KD, Takayasu’s arteritis and Giant Cell arteritis - coincided with their activation of the mechanistic target of rapamycin (mTOR) signalling pathway. Moreover, the genetic deletion of mTOR signalling in SMCs abrogated the emergence of intimal fibroblasts, demonstrating that mTOR is an intrinsic and essential regulator of vasculitis-induced, SMC-derived intimal fibroblasts. Collectively these findings provide molecular insight into the pathogenesis of arterial stenosis and identify mTOR as a therapeutic target to prevent adverse vascular remodelling in vasculitis.