Mechanisms of newborn pulmonary hypertension caused by chronic intrauterine hypoxia

慢性宫内缺氧引起新生儿肺动脉高压的机制

• 批准号: 10543507
• 负责人: Arlin B Blood
• 金额: $ 78.16万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10543507
• 关键词: Acclimatization; Address; Adult; Altitude; Animal Model; Animals; Antioxidants; Ascorbic Acid; Attenuated; Birth; Blood Vessels; Blood flow; Blood gas; Calcium; Cell Hypoxia; Chronic; Communication; Development; Disease; Electron Microscopy; Epigenetic Process; Exposure to; Fetal Development; Fetal Sheep; Fetus; Flow Cytometry; Functional disorder; Gene Expression; HIF1A gene; Hypoxia; Image; In Situ; In Vitro; Incidence; Iron; Link; Lung; Measures; Mediating; Methodology; Methods; MicroRNAs; Mitochondria; Modality; Molecular; Myography; Neonatal; Newborn Infant; Outcome; Oxidative Stress; Pathogenicity; Pathway interactions; Persons; Placental Insufficiency; Play; Potassium Channel; Pre-Eclampsia; Predisposing Factor; Pregnancy; Pregnancy Complications; Pregnant sheep; Production; Proteins; Pulmonary Hypertension; Pulmonary artery structure; Reactive Oxygen Species; Relaxation; Rodent; Role; Ryanodine Receptor Calcium Release Channel; Sheep; Stress; Sulfur; Sulofenur; Term Birth; Testing; Therapeutic; Tissues; Translations; Vasodilation; Work; antioxidant therapy; cigarette smoking; design; fetal; fetus hypoxia; genetic manipulation; gestational hypoxia; hypoxia inducible factor 1; in utero; in vivo; knock-down; lamb model; large-conductance calcium-activated potassium channels; mitochondrial dysfunction; mortality; neonatal outcome; neonatal pulmonary hypertension; novel; patch clamp; pharmacologic; postnatal; prevent; pulmonary function; response

PROJECT SUMMARY Chronic intrauterine hypoxia is common amongst not only the 140 million people in the world living at high altitudes but also in many complications of pregnancy such as preeclampsia, cigarette smoking, and placental insufficiency. Adaptation of the fetus to chronic hypoxia results in many adverse developmental outcomes, including pulmonary hypertension of the newborn. The BKCa channel is critical to the relaxation of the pulmonary vasculature of the newborn at birth. Recent results from our well-established fetal lamb model of chronic hypoxia during pregnancy points to BKCa channel dysfunction as a causal factor in pulmonary hypertension. The work in this proposal will investigate the mechanistic link between cellular hypoxia and BKCa channel dysfunction. Recent work by others indicates that the ‘master hypoxamir’ miR210, a micro-RNA that is upregulated by HIF-1?, orchestrates pulmonary hypertension by suppressing translation of the iron-sulfur cluster assembly protein ISCU. The resulting lack of iron-sulfur clusters results in mitochondrial dysfunction. We hypothesize that chronic intrauterine hypoxia leads to pulmonary hypertension by activation of the HIF-1? → miR210 → ISCU axis, resulting in increased mitochondrial-derived reactive oxygen species that lead to BKCa channel dysfunction. We propose three specific aims. Each specific aim is designed to integrate in vitro and in vivo approaches in order to better ascertain the relevance of the in vitro results to pulmonary function of the intact animal. Aim 1 will focus on determining the mechanism underlying BKCa channel dysfunction, and on establishing whether loss of BKCa channel function alone is adequate to result in pulmonary hypertension in intact lambs. Aim 2 will focus on the effects of hypoxia-induced increases in miR210 on ISCU activity, iron-sulfur cluster levels, and mitochondrial function and reactive oxygen species production. In intact lambs, we will establish whether activation of this pathway in the absence of hypoxia results in pulmonary hypertension, and whether suppression of this pathway in the presence of hypoxia prevents BKCa channel function and pulmonary hypertension. Aim 3 will investigate whether the increased reactive oxygen species levels in response to chronic hypoxia play a causative role in BKCa channel function and pulmonary hypertension. Using both in vitro and in vivo methods, we will determine whether the global antioxidant Vitamin C or mitochondria-specific antioxidant MitoQ will prevent pulmonary hypertension caused by chronic intrauterine hypoxia.

项目总结