Juvenile Exposure to High Fructose Diet in Pathogenesis of Adult Neurovascular Dysfunction - The World Health Organization estimates that morbidity due to cerebrovascular disease will increase by 15% over the next decade, resulting in more than 20 million years of healthy life lost globally. Importantly, we and others have shown that the pathogenesis of cerebrovascular disease can begin early in life, even during childhood, with adverse vascular phenotypes as important mechanisms underlying disease development. There remains a fundamental need to protect cerebrovascular health during childhood, as the early modifiable risk factors, like diet, may initiate vascular alterations that can begin to occur in childhood and increase the risk of cerebrovascular and cognitive decline in later life. Emerging evidence underscores the detrimental effects of high-sugar diets and hyperglycemia on cerebrovascular health in children; however, the mechanisms underlying the detrimental effects of high-sugar diets on cerebrovascular and cognitive function remain largely unknown. The proposed work will investigate the effects of an energetically neutral, high-fructose diet on 1) cerebrovascular risk factors, cerebral microvascular perfusion, cognition, and behavior, and 2) vascular reactivity and capillary function, in the rat brain at ages corresponding to early childhood through middle age. Our central hypothesis is that a high-fructose diet, even in the absence of weight gain, will progressively impair function of the neurovascular unit, leading to a reduction in cerebral microvascular function and related cognitive and behavioral decline in developing rats, ultimately resulting in significant microvascular, cognitive, and behavioral impairment in middle-aged rats. Aim 1 longitudinally determine the impact of early-life exposure to a high-fructose diet on blood pressure, arterial stiffness, oxygen perfusion, cognitive performance, and anxiety behavior in rats at 6, 8, and 16, and 36 weeks of age. Aim 2 will determine the effects of early-life exposure to a high-fructose diet on dynamic capillary perfusion, glycocalyx function, microvascular reactivity, and neural inflammation in rats at, 6, 8, 16, and 36 weeks of age. The parallel longitudinal and cross-sectional design of this study will provide novel information about the impact of a high-fructose diet on the neurovascular unit and cognitive function, both acutely (during development) and with continued exposure into middle age. This study will investigate, for the first time, the long-term impact of early consumption of high fructose on cerebrovascular perfusion, blood-brain barrier integrity, and neural inflammation, mechanisms that potentially underlie development of cerebrovascular disease and cognitive decline with advancing age.
