Mechanisms of the Age-related Alterations in Lymphatic Pumping

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DESCRIPTION (provided by applicant): The major task of the lymphatic system is lymph transport. This system of vessels and nodes is designed to transport fluid, soluble molecules and cells from the interstitium through the lymph nodes to the central veins. The lymphatic system plays important roles in body fluid circulation, macromolecular homeostasis, fat absorption, and immunity. Although all of these body systems are affected by aging, the effects of aging on the lymphatic transport component of any of these body functions are unknown. Particularly, very little is known about the age-related alterations of phasic contractions of the lymphatics, which are critical to the generation of lymph flow. Transporting lymphatics work in a "self-regulatory mode" when their contractility constantly adjusts to the local fluid loads through pressure and flow dependent regulatory mechanisms. The central hypothesis of this proposal is that aging modulates the pressure and flow-dependent regulatory mechanisms in lymphatics. This will result in a regression of the functional adaptive reserves in lymphatic contractility due to the eNOS/iNOS disbalances along with alterations in calcium sensitivity and crossbridge activation mechanisms in lymphatics. Such age-related changes in lymph transport system could diminish the ability of lymphatics to provide adequate lymph transport component for many body functions. The specific aims are: 1) To determine the age-related changes in the sensitivity of lymphatic vessels to transmural pressure and to evaluate their adaptive contractile reserves, 2) To determine the age-related changes in the active mechanical properties of the lymphatic vessels, 3) To determine the age-related changes in flow/walls shear stress profiles in situ and in their sensitivity to imposed flow in isolated lymphatic vessels, 4) To investigate the molecular mechanisms responsible for age-related alterations of lymphatic contractility and to develop an experimental model to improve the diminished lymphatic contractility in aged lymphatics. Mesenteric lymphatics and thoracic duct from 9 and 24 mo rats (Fischer-344 NIA) will be used for all proposed studies. We anticipate that changes in the contractile and regulatory protein components and/or endothelium cell dysfunction are the basis for the impaired pressure/flow-induced functional responses of the aged lymphatics. The results of this research will provide the missing link between the age- related processes in the different tissues and the age-related differential changes in the ability of lymphatics to provide the adequate transport of lymph from them in elderly organisms. Data from this proposal will also provide the basic knowledge for the ways to improve lymphatic transport that is compromised during aging. Narrative: These studies will provide important new information on how aging alters lymphatic pumping in the elderly. The development of the proposed experimental model, together with novel scientific knowledge obtained in these studies, will provide a scientific basis for the development of future therapies to treat the edema that commonly occurs in the elderly population, impairing the functioning of different tissues.