One Carbon Nutrients and Vascular Function

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My research program focuses on the biology of one carbon nutrients (also known as methyl nutrients). These nutrients play a role in one carbon metabolism and are functionally required for nucleic acid synthesis, NADPH generation, and S-adenosylmethionine (SAM) synthesis, a methyl donor that is used for methylation of DNA, RNA, proteins and phospholipids. We study the role of these nutrients in growth and development and how dietary imbalances in these nutrients affect metabolic and physiological processes. Our Discovery Grant research (held 2009-2019) has identified: novel/non-traditional roles for one carbon nutrients in body composition, glucose homeostasis, brain, and vascular function; sex-specific effects of high maternal folic acid intakes with suboptimal vitamin B12 status during pregnancy/lactation on adult offspring physiology/metabolism; tissue-specific effects of one carbon nutrients on DNA methylation and gene expression; and imbalances in dietary one carbon nutrient intakes and status in women and children. In the next funding period, we propose to delineate the role of one carbon nutrients in vascular endothelial function. Vascular endothelial cells line the lumen of blood vessels and function in regulating how vessels respond to vasodilatory, mitogenic, and thrombogenic cues. Nitric oxide is one of the key signalling molecules regulating endothelial cell function. Endothelial nitric oxide synthase (eNOS) synthesizes nitric oxide from arginine using tetrahydrobiopterin (BH4), flavin mononucleotide (FMN)/flavin adenine dinucleotide (FAD), and nicotinaminde adenine dinucleotide phosphate (NADPH) as cofactors. Through BH4 and FMN/FAD, eNOS and nitric oxide synthesis are metabolically linked to folate and riboflavin metabolism. Our preliminary data suggest that vascular endothelial cell folate metabolism plays a role in vascular endothelial function and is unique and not reflected in liver and plasma. However, little is known about the metabolism of riboflavin and folate in endothelial cells and how dietary intakes of these nutrients directly affect vascular endothelial function. Studies proposed in our renewal application will address these knowledge gaps in the following objectives: 1) To determine if riboflavin status regulates vascular endothelial function. 2) To determine if riboflavin interacts with folate to regulate vascular function. 3) To determine if gestational riboflavin status programs adult vascular function. The long-term vision of my research program is that by characterizing the physiological effects of one carbon nutrients in mammalian systems, we will generate data that will: (a) contribute key information about optimal one carbon nutrients in the food supply and animal feeds; (b) address the safety of one carbon nutrient fortification policies in Canada's food supply; and (c) identify and characterize novel/non-traditional roles for these essential nutrients in physiological processes.