The overall purpose of the proposed study is to continue to explore the physiologic and biochemical mechanisms of contractility in small arteries of the fetal and adult cerebrovasculature, and the mechanisms by which cerebral vessels acclimatize to high altitude long-term hypoxia (LTH). In concert with these studies, we will continue to examine the mechanisms by which vascular contractility changes with development. These studies are of vital importance for both growth of the brain and its survival, as well as for long-term well-being of the developing infant and adult. Cerebrovascular homeostasis critically depends upon the responsiveness of cerebral arteries to a variety of physiologic and pathophysiologic stimuli. Particularly important among these are norepinephrine and other biogenic amines which mediate changes in cerebrovascular perfusion in response to stress, hemorrhage, and hypoxia/ischemia. Dysregulation of cerebral blood flow in the developing fetus and newborn is associated with intraventricular and germinal matrix hemorrhage, and related problems. At high altitude the adult cerebral circulation is vulnerable to high altitude cerebral edema, and thus may play a role in acute mountain sickness. Unfortunately, our current understanding of the fundamental mechanisms that underlie cerebrovascular homeostasis, from the standpoint of either development or long-term hypoxia, is quite limited. During the past decade, our studies have revealed important differences in the fundamental mechanisms that regulate cerebrovascular contractility in the fetus, as compared to the adult. These include unique features of calcium (Ca2+)-dependent receptor-second messenger coupling with plasma membrane potassium (K+)- and Ca2+-channels, and the virtual dependence of the immature organism on extracellular Ca 2+(as opposed to intracellular Ca 2+ stores in the adult) for Ca2+-dependent thick (myosin) filament regulation. Additionally of importance, we have discovered that the non-Ca2+-dependent pathway of protein kinase C (PKC) to specific enzymes in the mitogen activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) cascade, and their downstream effectors, caldesmon, calponin, and myosin light chain20 is markedly attenuated or down-regulated in the fetal cerebrovasculature, as compared to the adult. The proposed studies are important because they relate to the vulnerability of the fetal, newborn, and adult cerebrovasculature and brain to hypoxia/ischemia. In addition, they relate to the problem of prenatal """"""""programming"""""""" of adult disease. Finally, in adults and children they are of critical importance in understanding basic mechanisms of acute mountain sickness and high altitude cerebral edema. The central hypothesis is that the changes in cerebrovascular contractile responses in high-altitude acclimatized fetuses and adults are secondary to up-regulation of the MAPK/ERK pathway, in concert with other alterations in elements of the signal transduction cascade, We also hypothesize that such up-regulation will play a particularly important role in maturation of the fetal arteries. To test these hypotheses, we will perform studies in cerebral arteries of near-term fetuses (approximately 140 gd) and adult sheep that have been acclimatized to high altitude for 3 to 4 months, and also in sea level controls. To address the issue of long-term hypoxia, each of the these studies will be performed in vessels of both normoxic control and LTH animals. To address the effect of maturation, each will be examined in cerebral arteries of two groups, near-term fetus and nonpregnant adult animals.
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