CHRONIC HYPOXIA EFFECTS ON CAROTID CHEMORECEPTION

慢性缺氧对颈动脉化学感受的影响

• 批准号: 2891560
• 负责人: SALVATORE J FIDONE
• 金额: $ 25.34万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-07-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2891560
• 关键词: animal genetic material tag; atrial natriuretic peptide; cardiovascular function; carotid body; cell growth regulation; chronic disease /disorder; endothelin; environmental adaptation; gene induction /repression; growth factor receptors; hormone receptor; hormone regulation /control mechanism; hypoxia; laboratory rat; nitric oxide; receptor expression; tissue /cell culture; vascular endothelial growth factors

DESCRIPTION (Applicant's abstract): The mammalian carotid body, an arterial chemosensory organ, is comprised of specialized chemosensory type I cells and supportive type II cells embedded in a dense network of fenestrated capillaries and sinusoids. In response to natural stimuli (e.g., hypoxia, hypercapnia), type I cells release multiple neurotransmitter agents which excite chemoafferent nerve terminals of the carotid sinus nerve. The carotid body is the primary sensor for dissolved O2 in arterial blood, and as such, it is essential for the ventilatory acclimatization, which occurs during prolonged exposure to high altitude, and in a variety of other physiological and pathological states involving acute and chronic hypoxemia. In response to chronic hypoxia (CH), the carotid body undergoes remarkable morphological changes, including hypertrophy and hyperplasia of type I cells, and a dramatic increase in blood vessel volume (neo-vascularization). In addition, there is a gradual increase in chemosensitivity to hypoxia. Virtually nothing is known about the cellular mechanisms, which mediate these changes. Based upon our preliminary data, we hypothesize that four substances, all endogenous to the carotid body, are intimately involved in the tissue remodeling and reshaping as well as the increased chemosensitivity, which occurs during CH. These substances are vascular endothelial growth factor (VEGF), endothelin (ET), atrial natriuretic peptide (ANP) and nitric oxide (NO). They have in common vascular, mitogenic and neuro-regulatory properties. Using molecular biological, immunocytochemical, electrophysiological and neurochemical techniques, our proposed studies will explore: I. The effects of CH on the expression of these four substances and their receptors in the carotid body; II. Their role in tissue growth and tissue remodeling in the CH carotid body; III. Their up-regulation and contribution to the altered chemosensitivity which follows CH; and IV. The effects of CH on the cellular signaling mechanisms mediated by VEGF, ET, ANP and NO in this chemoreceptive tissue.

描述(申请人摘要)：哺乳动物颈动脉小体，动脉 化学感觉器官由特化的I型化学感觉细胞组成 和支持性II型细胞嵌入致密的有窗孔的网络 毛细血管和血窦。响应于自然刺激(例如，缺氧， 高碳酸血症)，I型细胞释放多种神经递质制剂， 兴奋颈动脉窦神经的化学传入神经末梢。这个 颈动脉小体是动脉血中溶解氧的主要传感器，并且 因此，这对于发生的呼吸习服是至关重要的。 在长时间暴露在高海拔环境中，以及在各种其他 涉及急性和慢性低氧血症的生理和病理状态。 作为对慢性低氧的反应，颈动脉小体经历了显著的 形态改变，包括I型肥大和增生症 细胞数量增加，血管体积急剧增加(新生血管形成)。 此外，对低氧的化学敏感性也在逐渐增加。 实际上，人们对细胞机制一无所知，而细胞机制是 这些变化。根据我们的初步数据，我们假设有四个 所有内源性物质都与颈动脉小体密切相关。 组织重塑和重塑以及增加的 对化疗的敏感性，发生在CH.这些物质是血管物质 血管内皮细胞生长因子、内皮素、心钠素 多肽(ANP)和一氧化氮(NO)。它们有共同的血管， 有丝分裂和神经调节特性。利用分子生物学， 免疫细胞化学、电生理和神经化学技术，我们的 拟议的研究将探索：I.CH对HSP70基因表达的影响 这四种物质及其在颈动脉小体的受体；II.它们的 颈动脉小体在组织生长和组织重塑中的作用 它们的上调和对化疗敏感性改变的贡献 紧随CH；和IV.CH对细胞信号机制的影响 由血管内皮生长因子、内皮素、心钠素和一氧化氮在该趋化组织中介导。