Intrauterine chronic hypoxia and ryanodine receptors in fetal pulmonary arteries

宫内慢性缺氧与胎儿肺动脉兰尼碱受体

基本信息

批准号：
8303998
负责人：
SEAN M WILSON
金额：
$ 7.43万
依托单位：
LOMA LINDA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8303998
关键词：
Acute Altitude Alveolar Arteries Biology Birth Blood Vessels Cardiovascular Diseases Cell membrane Cells Chronic Climacteric Data Development Disease Down-Regulation Endothelium Enzyme-Linked Immunosorbent Assay Exposure to Fetus Functional disorder Goals Growth Heart Diseases Human Hypertension Hypoxemia Hypoxia Individual Infant Investigation Laser Scanning Confocal Microscopy Life Link Lung Lung diseases Malnutrition Measures Mediating Metabolic Diseases Modeling Molecular Muscle Cells Myopathy Neurons Outcome Pathogenesis Pathology Pathway interactions Penetration Photometry Pilot Projects Placental Insufficiency Populations at Risk Pregnancy Process Protein Isoforms Publishing Pulmonary Circulation Pulmonary Edema Pulmonary Hypertension Pulmonary artery structure Relaxation Research Risk Role Ryanodine Receptors Series Sheep Signal Transduction Site Skeletal Muscle Smoking Stress Techniques Testing Therapeutic Intervention Time Up-Regulation Vascular Diseases Vascular Smooth Muscle Vasoconstrictor Agents Western Blotting Work base constriction expectation fetal fetal programming innovation mRNA Expression malformation neonatal pulmonary hypertension novel pressure protein expression receptor response treatment strategy vasoconstriction

项目摘要

DESCRIPTION (provided by applicant): Intrauterine stress can induce long-lived changes in function that predispose the fetus for disease throughout life. Maternal hypoxemia due to high altitude living, placental insufficiency, and smoking puts infants of certain populations at risk o developing pulmonary hypertension, high altitude pulmonary edema, and increases the risk for development of idiopathic pulmonary hypertension later in life. Gestation at high altitude causes a variety of pulmonary vascular malformations in fetal sheep including suppressed endothelium dependent relaxation, altered myocyte growth, and reactivity that place them at risk of developing hypertension after birth. Indeed, high altitude gestation and birth exaggerates hypoxia induced pulmonary vasoconstriction in 2 week old sheep and results in significant penetration of pulmonary hypertension. Sheep are therefore a relevant model for understanding novel pathways and mechanisms associated with fetal origins of pulmonary vascular disease because hypoxemia due to high altitude gestation recapitulates disease found in humans. The fundamental focus is that ryanodine receptors (RyR) are central to the process of pulmonary arterial constriction in response to acute alveolar hypoxia, which can be dysregulated in individuals with pulmonary hypertension. Three RyR isoforms are known, and all three are vital to the intrinsic vasoconstrictor response to acute hypoxia in pulmonary arteries. RyR channelopathies actively participate in the pathogenesis of neuronal, skeletal muscle, cardiac, and vascular diseases and yet their role in fetal programming of pulmonary vascular disease is unknown. The central hypothesis of this project is that high altitude gestation will suppress RyR-mediated local Ca2+ "sparks" and global Ca2+ responses due to acute hypoxia and that these responses will be manifested by reductions in RyR expression. We propose this counterbalances mechanisms that would increase vascular contraction to acute hypoxia. This would help reduce the extent of pulmonary hypertension due to long-term intrauterine hypoxia. The central hypothesis is based on published and preliminary studies performed with full-term fetal sheep. We plan to test our central hypothesis by pursuing two Specific Aims. Specific Aim 1 will determine whether high altitude gestation suppresses the expression of the three RyR isoforms. Specific Aim 2 will determine the corresponding reduction in RyR mediated Ca2+ responses and pulmonary vasoconstriction in response to acute hypoxia. The hypotheses will be examined by performing molecular, histochemical, and functional studies in pulmonary arteries from term-fetal lambs. With regards to the expected outcomes, the work proposed is expected to identify the influence of long-term intrauterine hypoxia on RyR function in the fetus. These studies are expected to fundamentally advance the field of pulmonary vascular biology by associating RyRs with pulmonary vascular disease. Such results will provide an important positive impact, because RyRs are highly likely to provide novel targets for therapeutic interventions in the treatment of pulmonary vascular disease. PUBLIC HEALTH RELEVANCE: The investigations we propose help provide a mechanistic basis for the role of long-term intrauterine hypoxia in the development of pulmonary hypertension in the newborn. The goal of these studies is to associate ryanodine receptors with disease pathogenesis. Such results will provide an important positive impact, because ryanodine receptors are highly likely to provide novel targets for therapeutic interventions.

描述（由申请人提供）：宫内应激可引起长期的功能变化，使胎儿在一生中容易患病。高原生活、胎盘功能不全和吸烟导致的母亲低氧血症使某些人群的婴儿面临发生肺动脉高压、高原肺水肿的风险，并增加日后发生特发性肺动脉高压的风险。高海拔妊娠会导致胎羊出现多种肺血管畸形，包括抑制内皮依赖性舒张、改变肌细胞生长以及使它们在出生后面临患高血压风险的反应性。事实上，高原妊娠和出生会加剧两周龄绵羊缺氧引起的肺血管收缩，并导致肺动脉高压的显着渗透。因此，绵羊是了解与肺血管疾病胎儿起源相关的新途径和机制的相关模型，因为高海拔妊娠引起的低氧血症重现了人类中发现的疾病。基本焦点是兰尼碱受体（RyR）是响应急性肺泡缺氧而导致的肺动脉收缩过程的核心，肺动脉高压患者的肺动脉缺氧可能会失调。已知三种 RyR 亚型，这三种亚型对于肺动脉急性缺氧的内在血管收缩反应至关重要。 RyR 通道病积极参与神经元、骨骼肌、心脏和血管疾病的发病机制，但其在肺血管疾病胎儿编程中的作用尚不清楚。该项目的中心假设是，高海拔妊娠将抑制 RyR 介导的局部 Ca2+“火花”和由于急性缺氧而引起的全身 Ca2+ 反应，并且这些反应将通过 RyR 表达的减少来体现。我们提出这种平衡机制会增加血管收缩以导致急性缺氧。这将有助于减轻因长期宫内缺氧而引起的肺动脉高压的程度。中心假设基于已发表的对足月胎羊进行的初步研究。我们计划通过追求两个具体目标来检验我们的中心假设。具体目标 1 将确定高海拔妊娠是否抑制三种 RyR 同工型的表达。具体目标 2 将确定 RyR 介导的 Ca2+ 反应和急性缺氧引起的肺血管收缩的相应减少。这些假设将通过对足月胎羔的肺动脉进行分子、组织化学和功能研究来检验。关于预期结果，拟议的工作预计将确定长期宫内缺氧对胎儿 RyR 功能的影响。这些研究有望通过将 RyR 与肺血管疾病联系起来，从根本上推进肺血管生物学领域的发展。这样的结果将产生重要的积极影响，因为 RyR 很可能为肺血管疾病的治疗干预提供新的靶点。公共卫生相关性：我们提出的研究有助于为长期宫内缺氧在新生儿肺动脉高压发展中的作用提供机制基础。这些研究的目的是将兰尼碱受体与疾病发病机制联系起来。这样的结果将提供重要的积极影响，因为兰尼定受体很可能为治疗干预提供新的靶点。