LAUSR

Intracranial atherosclerotic stenosis (ICAS), the most common cause of stroke worldwide, is associated with high risk of recurrent ischemic stroke. F-box and WD repeat domain containing protein 7 (FBW7), an ubiquitin E3 ligase, is recently suggested to be involved in atherogenesis. However, whether FBW7 affects cerebrovascular remodeling during ICAS remains unknowns. We found that the expression of FBW7 was decreased in mouse brain microvessels from high-fat diet (HFD)-fed atherosclerotic mice. The reduced FBW7 expression was negatively associated with the remodeling of middle cerebral artery (MCA). Specific loss of FBW7 in smooth muscle cells (SMCs) markedly potentiated brain vascular SMC (VSMC) proliferation, migration and subsequent MCA remodeling in atherosclerotic mice. The increase of total reactive oxygen species (ROS) generation and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity in brain microvessels and VSMCs were enhanced after knockout of FBW7, while the mitochondria-derived ROS was unchanged. Analysis of several key subunits of NADPH oxidase revealed that FBW7 deficiency augmented HFD-induced the increase of Nox1 expression, but had no effect on p47phox and p67phox phosphorylation as well as p22phox expression. Both NADPH oxidase specific inhibitor and Nox1 downregulation abrogated the effects of FBW7 deficiency on MCA remodeling. Immunoprecipitation assay identified that FBW7 interacted with Nox1. FBW7 knockout increased Nox1 protein stability by inhibiting ubiquitin-mediated degradation. Collectively, our study demonstrates that SMC-specific deficiency of FBW7 exacerbates ICAS by facilitating Nox1-derived ROS generation, VSMC proliferation and cerebrovascular remodeling.