Cerebrovascular contractile responses to high altitude

高海拔脑血管收缩反应

• 批准号: 6875421
• 负责人: LAWRENCE D LONGO
• 金额: $ 16.2万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6875421
• 关键词: age difference; altitude; brain edema; cardiovascular function; cerebral artery; cerebrovascular system; dysbarism; embryo /fetus; embryo /fetus hypoxia; environmental adaptation; hypoxia; sheep; vasoconstriction

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.

本研究的总体目的是继续探讨胎儿和成人脑血管小动脉收缩的生理生化机制，以及脑血管适应高原长期缺氧（LTH）的机制。与这些研究相一致，我们将继续研究血管收缩力随发育而变化的机制。这些研究对于大脑的生长和生存以及发育中的婴儿和成人的长期福祉至关重要。脑血管稳态很大程度上取决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，它们介导脑血管灌注变化以响应应激、出血和缺氧/缺血。发育中的胎儿和新生儿的脑血流失调与脑室内和生发基质出血以及相关问题有关。在高原地区，成人脑循环易发生高原脑水肿，因而可能在急性高山病中发挥作用。不幸的是，我们目前对脑血管稳态基本机制的理解，无论是从发育还是长期缺氧的角度来看，都是相当有限的。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力的基本机制存在重要差异。其中包括独特的 钙 (Ca2+) 依赖性受体第二信使与质膜钾 (K+) 和 Ca2+ 通道耦合的特征，以及未成熟生物体对细胞外 Ca 2+（与成人细胞内 Ca 2+ 储存相反）进行 Ca2+ 依赖性粗（肌球蛋白）丝调节的虚拟依赖。此外，重要的是，我们发现蛋白激酶 C (PKC) 与丝裂原激活蛋白激酶 (MAPK)/细胞外信号调节激酶 (ERK) 级联中特定酶的非 Ca2+ 依赖性途径及其下游效应子钙结合蛋白、钙调蛋白和肌球蛋白轻链 20 在胎儿中显着减弱或下调 脑血管系统，与成人相比。拟议的研究很重要，因为它们涉及胎儿、新生儿和成人脑血管系统和大脑对缺氧/缺血的脆弱性。此外，它们还涉及成人疾病的产前“编程”问题。最后，对于成人和儿童来说，它们对于了解急性高山病的基本机制至关重要 以及高原脑水肿。 核心假设是，适应高原环境的胎儿和成人脑血管收缩反应的变化继发于 MAPK/ERK 通路的上调，与信号转导级联元件的其他变化相一致。我们还假设这种上调将在胎儿动脉的成熟中发挥特别重要的作用。为了检验这些假设，我们将对已适应高海拔 3 至 4 个月的近期胎儿（约 140 gd）和成年羊的脑动脉以及海平面控制进行研究。为了解决长期缺氧的问题，这些研究中的每一项都将在 常氧对照和 LTH 动物的血管。为了研究成熟的影响，将对两组（近足月胎儿和非妊娠成年动物）的脑动脉进行检查。