Vascular remodeling is a critical process in the pathogenesis of diseases of outstanding clinical importance, such as atherosclerosis, restenosis, saphenous vein graft occlusion, and transplant-associated arteriosclerosis. Factors that control the activities of vascular smooth muscle cells (SMCs), key contributors to vascular remodeling, remain incompletely understood. Fat cadherins belong to an ancient family of proteins found throughout Metazoans; conserved functions of these proteins affect cell growth and polarity, and span from Drosophila to mammals. We have found that the FAT1 cadherin is expressed by SMCs in multiple animal models of vascular disease and in injured human arteries. In recent work, we reported that loss of FAT1 expression in SMCs permits a dramatic increase in proliferation and neointimal formation in a mouse model of vascular injury; similarly, preliminary studies in atherosclerotic models show larger plaques when SMC FAT1 is lacking.Although FAT1 has a type I transmembrane protein structure, it undergoes complex processing. In an affinity purification/interaction screen, we found that the FAT1 intracellular domain (ICD) associates with mitochondrial proteins, and that fragments of the FAT1ICD accumulate within mitochondria, wherein they interact selectively with inner mitochondrial membrane proteins and exert control over oxidative phosphorylation, limiting the activities of respiratory Complexes I and II and inhibiting cell growth. This novel mechanism provides a distinctive and relatively direct way to relay information from the cell surface and to the inner mitochondrial membrane to affect SMC metabolism.SMC metabolism and its significance for vascular remodeling are not well understood. We have outlined the framework of the FAT1-mitochondrial pathway, but critical mechanistic aspects and the broader molecular context that shapes pathway activity remain unclear. We hypothesize that FAT1-mediated control of SMC mitochondrial respiration and overall cellular metabolism contribute importantly to vascular remodeling. Our studies will address basic understanding of this new FAT1-mitochondrial pathway. We want to learn how FAT1 is cleaved, how FAT1ICD location within cells affects its interaction with other growth related signaling pathways, and whether this is important for growth regulation in vivo. The new knowledge gained will inform strategies to manipulate the FAT1 pathway for therapeutic benefit in vascular disease.
|Program type||Transformational Project Award|
|Effective start/end date||07/01/2019 → 06/30/2022|