Aging and Hepatic Microvascular Dysfunction

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DESCRIPTION (provided by applicant): Aging of the liver is associated with reductions in its mass as well as a 30-50% reduction in blood flow accompanied by an impaired metabolism and potential clinical implications including adverse drug reactions, susceptibility to toxins, and atherosclerosis. The reason for this age related reduction in hepatic blood flow is not known. However, significant age associated reductions in the fenestration of hepatic sinusoidal endothelial cells (SEC) and increased deposition of extracellular matrix, basal lamina, and connective tissue in the Space of Disse leading to "pseudocapillarization" of the SEC are thought to affect the transfer of substrates including oxygen, chylomicron remnants, toxins, and drugs between the blood and hepatic parenchymal cells. What functional alterations in SEC accompany "pseudocapillarization" are not clear but may play a significant role in the age related diminished blood flow. Accumulation of advanced glycation end-products (AGEs) also occurs with aging in SEC, but its effects on SEC and microvascular function are unknown. We hypothesize that age associated reductions in hepatic blood flow and SEC morphology are due the accumulation of AGE in these cells causing reduced production of constitutive nitric oxide (NO) and/or enhanced production of endothelin-1 (ET-1) and sinusoid constriction perhaps accompanied by an hepatic microvascular inflammatory response. To validate this hypothesis, the livers of mice will be studied at 0.8, 3.3,14, and 27 months of age. In vivo microscopy will be used to determine the dynamic spatial and temporal development of hepatic microvascular dysfunction. Light and electron microscopic examination of fixed specimens and isolated SEC will evaluate structural alterations that can not be visualized in vivo. These will be correlated with measurements of the accumulation of AGE in SEC and changes in NO, eNOS, ET-1, proinflammatory cytokines, and superoxide in SEC and liver to gain clues to explain the responses observed microscopically. The results should provide novel, new information about the aging liver.