Leukocyte-Endothelium Interactions in Aging

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The present research proposal will examine whether that the phenotypic modifications of the vascular endothelium that occur with aging damage the regulatory mechanisms of the inflammatory response by impairing leukocyte-endothelium interaction in the microcirculation. Pathologic leukocyte-endothelium interactions are implicated in the pathophysiology of acute and chronic cardiovascular diseases, such as stroke, coronary artery disease, myocardial infarction, and atherosclerosis. Leukocyte- endothelium interactions also play a key role in the immunologic response, in the defense against infectious diseases, and in the immunosurveillance. The elderly suffer a higher morbidity and mortality from vardiovascu7lar disease. As a result of immuno senescence, the elderly also have higher incidence of infectious diseases, cancer, and autoimmune diseases. Data are not currently available regarding the effect of aging on the dynamic interactions between circulating leukocytes and endothelial cells in the microcirculation. To test our hypothesis, the following three questions highly relevant to the biology of aging need to be addressed: 1. Does aging alter the physiological processes that regulate leukocyte- endothelium interaction in the microcirculation? 2. Does aging change the expression of cell adhesion molecules on endothelial cells and circulating leukocytes? 3. Does aging cause endothelial dysfunction in the microcirculation as it has been demonstrated in large conduit arteries of aged animals and humans? To address the above questions we will use intravital microscopy to study leukocyte-endothelium interactions in the mesenteric microcirculation of aged rats. We will study the expression of cell adhesion molecules on endothelial cells and circulating leukocytes. We will measure levels of nitric oxide in the microcirculation of aged rats in vivo. Overall, the present research proposal is designed to gain the necessary preliminary information for a future more extensive research application focusing on: a) the physiologic and molecular mechanisms of a leukocyte-endothelium interactions in aging and b) the design therapeutic strategies to preserve endothelial and immunologic functions in the aged organism. The overall goal is to identify biological markers of aging and to help developing intervention strategies to delay or prevent senescence of the cardiovascular and immune systems.