Cerebrovascular contractile responses to high altitude

本研究的总体目的是继续探索胎儿和成人脑血管小动脉收缩性的生理生化机制，以及脑血管对高原长期缺氧（LTH）的适应机制。与这些研究相一致，我们将继续研究血管收缩力随发育变化的机制。这些研究对于大脑的生长和存活，以及发育中的婴儿和成人的长期健康都至关重要。脑血管内稳态严重依赖于脑动脉对各种生理和病理生理刺激的反应。其中特别重要的是去甲肾上腺素和其他生物胺，它们介导应激、出血和缺氧/缺血时脑血管灌注的变化。发育中的胎儿和新生儿脑血流失调与脑室内和生发基质出血及相关问题有关。在高海拔地区，成人脑循环容易发生高原脑水肿，因此可能在急性高原病中起作用。不幸的是，从发育或长期缺氧的角度来看，我们目前对脑血管内稳态的基本机制的理解相当有限。在过去的十年中，我们的研究揭示了与成人相比，胎儿调节脑血管收缩性的基本机制存在重要差异。这些包括独特的

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.