We plan to investigate the role of growth hormone and insulin-like growth factor-1 in the long-term regulation of cerebral blood vessels. Our hypotheses are: 1) that the total number of cerebral vessels decreases and become more tortuous with age, 2) that growth hormone replacement (infusion of growth hormone releasing factor -GRF) will reduce the age- related rarefaction of cerebral vessels, 3) that the """"""""brain protective"""""""" effect of GRF infusion pulses is due to growth hormone acting directly on IGF-1 production in vascular tissue, and that locally produced IgF-1 has been autocrine and paracrine action to facilitate the repair and maintenance of local vascular and neural tissue. To test these hypotheses we will document the cerebral microvascular and systemic hemodynamic changes that occur with aging. We will determine the number, diameter, length, tortuosity, anastomoses and vasomotion parameters (frequency and amplitude) of cerebral arterioles and venules along with measurements of cortical width (an index of cortical thickness). Correlations will be made with measured plasma levels of IGF-1, each month in each age group. Cortical arteriolar vascular reactivity will be assessed utilizing CO2 challenges. We will investigate the role of circulation growth hormone in the maintenance of the cerebral vasculature by: a) observing the ability of growth hormone releasing factor (GRF) infusion pulses to reverse the previously documented age-related microvascular alterations and to support maintenance of microvessel structure, and b) determining the location and expression of growth hormone receptors in the vasculature of the cortical surface,using in situ hybridization techniques for growth hormone mRNA and receptor binding studies. We will determine the importance of local IGF-1 production in the mechanism f the previously described age-related microvascular changes by assessing IGF-1 and type 1 IGF receptor dynamics in control animals and following GRF administration, by performing the following experiment: At the end of each experimental observation period, we will assess the expression of IGF-1 and type 1 IGF receptor mRNA in surface vascular elements of the brain using in situ hybridization as well as the distribution of IGF-1 using immunocytochemistry and type 1 IGF receptors by receptor binding. These investigations will contribute to a better understanding of age- related microvascular alterations in the brain. In combination with the other projects of this program, extrapolations may be made concerning the clinical manifestations of cerebral microvessel pathology, such as vascular dementias.
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