Cerebrovascular contractile responses to high altitude long term hypoxia

高海拔长期缺氧的脑血管收缩反应

基本信息

批准号：
7755429
负责人：
LAWRENCE D LONGO
金额：
$ 19.8万
依托单位：
LOMA LINDA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7755429
关键词：
Acclimatization Actins Acute Address Adrenergic Agents Adrenergic Receptor Adult Affinity Altitude Altitude Sickness Animals Arteries Attenuated Biochemical Biogenic Amines Blood Vessels Brain Brain Hypoxia-Ischemia Calcium Cell membrane Cerebral Edema Cerebrovascular Circulation Cerebrum Child Coupling Dependence Development Disease Down-Regulation Elements Enzymes Extracellular Signal Regulated Kinases Fetus Filament Growth Hemorrhage Homeostasis Hypoxemia Hypoxia Indium Individual Infant Inositol Intraventricular Light Measures Mediating Microfilaments Mitogen-Activated Protein Kinases Myosin ATPase Newborn Infant Norepinephrine Organism Pathway interactions Perfusion Perinatal subependymal hemorrhage Personal Satisfaction Physiological Play Potassium Protein Kinase C Regulation Rho-associated kinase Role Sea Second Messenger Systems Secondary to Sheep Signal Transduction Stimulus Stress Testing Thick Up-Regulation adrenergic caldesmon calponin cerebral artery cerebrovascular citrate carrier density extracellular fetal mature animal middle cerebral artery prenatal programs receptor response rho second messenger virtual

项目摘要

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.

拟议的研究的总体目的是继续探索胎儿和成人脑血管造成的小动脉中收缩力的生理和生化机制，以及脑血管适应于高海拔长期低氧（lth）的脑血管的机制。与这些研究一致，我们将继续研究血管收缩性随发育而变化的机制。这些研究对于大脑的生长及其生存以及发育中的婴儿和成人的长期福祉至关重要。脑血管稳态严格取决于脑动脉对各种生理和病理生理刺激的反应。在其中尤其重要的是去甲肾上腺素和其他生物胺，这些胺可介导响应压力，出血和低氧/缺血的脑血管灌注的变化。发育中的胎儿和新生儿中脑血流的失调与脑室室内和生发基质出血以及相关问题有关。在高海拔地区，成年脑循环容易受到高海拔大脑水肿的影响，因此可能在急性山上疾病中发挥作用。不幸的是，从发育或长期缺氧的角度来看，我们目前对脑血管稳态基础的基本机制的理解非常有限。在过去的十年中，与成年人相比，我们的研究揭示了调节胎儿脑血管收缩力的基本机制的重要差异。这些包括唯一钙（Ca2+）的特征 - 依赖受体秒通信与质膜钾（K+） - 和Ca2+ - 通道以及不成熟有机体对细胞外Ca 2+的虚拟依赖性（与ca2+依赖性浓度的ca2+ - 依赖性浓度相反）。另外，我们已经发现，蛋白激酶C（PKC）的非CA2+依赖性途径与有丝分裂原活化蛋白激酶（MAPK）/细胞外信号调节激酶（ERK）级联酶（ERK）级联酶（ERK）的特定酶的特定酶，并在下游效应子中，caldesmon，Caldesmon，caldesmon light 20 IS caldesmon light 20与成年人相比，脑血管形系统。拟议的研究很重要，因为它们与胎儿，新生儿和成人脑血管形和大脑对低氧/缺血的脆弱性有关。此外，它们与成人疾病的产前“编程”有关。最后，在成人和儿童中，它们对于理解急性山疾病的基本机制至关重要和高海拔大脑水肿。核心假设是，高空适应的胎儿和成年人中脑血管收缩反应的变化是继发于MAPK/ERK途径上调的继发的，与信号传输级联级联元素的其他变化一致，我们还假设这样的上调在胎儿的成熟中起着特别重要的作用。为了检验这些假设，我们将在近期胎儿（约140 GD）和成年绵羊的脑动脉中进行研究，这些绵羊已适应高海拔3至4个月，并且在海平面控制中。为了解决长期缺氧的问题，这些研究都将在正常氧对照和LTH动物的血管。为了解决成熟的影响，将在两组近期胎儿和非怀孕的成年动物的脑动脉中进行检查。