Metabolic control in vascular remodeling

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Summary Vascular remodeling is essential for artery formation during embryogenesis and in the pathogenesis of vascular diseases such as atherosclerosis, restenosis, and transplant- associated arteriosclerosis in adulthood. Despite this high clinical significance, our incomplete understanding of the process of vascular remodeling limits current abilities to develop preventive and therapeutic strategies. Vascular smooth muscle cells (SMCs) are main drivers of developmental and adult vascular remodeling, but mechanisms underlying SMC activities are not fully elucidated — in particular, the role of mitochondria and metabolism in this context is relatively unexplored. The goal of this proposal is to understand mitochondrion-based mechanisms that regulate SMC phenotype in vascular remodeling. We have shown that the FAT1 cadherin interacts with and inhibits mitochondrial respiratory complex I, limits SMC proliferation by restraining mitochondrial respiration, and opposes vascular occlusion after arterial injury. These findings suggest that respiratory complex I regulates SMC behavior. Our new preliminary data further support this idea. Loss of complex I subunit NDUFS4 in cultured SMCs decreases complex I levels and activity, limits the formation of supercomplexes containing complex I, lowers aspartate levels, and impairs cell growth. In vivo, NDUFS4 is highly expressed during mouse development in SMCs building the arterial wall, and in adult mice in SMC-derived cells that form the expanding neointima that accumulates in response to arterial injury. Preliminary studies with selective NDUFS4 deletion in SMCs suggest that these cells require respiratory complex I for normal embryogenesis. We hypothesize that complex I promotes SMC activities important for vascular remodeling during embryogenesis and in adulthood. We will test this hypothesis in three specific aims that respectively address the effects of impaired respiratory complex I function 1) on key SMC activities, 2) on mouse vascular development, and 3) in models of adult vascular homeostasis, injury, and atherosclerotic disease. These studies will add a new respiratory complex-based angle — susceptible to pharmacological intervention — to our understanding of how arteries form and how they respond to injury, with relevance for tissue engineering, therapeutic angiogenesis, tumor vascularization, and vascular disease.