Impaired Endothelial Maturation and the Developmental Origin of Vascular Disease

内皮成熟受损和血管疾病的发育起源

• 批准号: 9085330
• 负责人: NICHOLAS A FLAVAHAN
• 金额: $ 33.28万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9085330
• 关键词: Actins; Adherens Junction; Adult; Adult Children; Angiotensin II; Angiotensins; Animal Model; Animals; Arteries; Barker Hypothesis; Birth; Blocking Antibodies; Blood Pressure; Blood Vessels; Cardiovascular Diseases; Cardiovascular Pathology; Cardiovascular Physiology; Cardiovascular system; Cell Line; Cell physiology; Cells; Characteristics; Data; Defect; Deterioration; Development; Diabetes Mellitus; Dilator; Disease; Endothelial Cells; Endothelin; Endothelium; Epidemiologic Studies; Epidemiology; Event; Fetal Growth Retardation; Functional disorder; Generations; Gestational Age; Health; Hypertension; Individual; Infant; Mediating; Mediator of activation protein; Metabolic Diseases; Metabolism; Modeling; Neonatal; Newborn Infant; Non-Insulin-Dependent Diabetes Mellitus; Phenotype; Process; Production; Proteins; Renin; Research; Risk; Role; Signal Transduction; Small for Gestational Age Infant; Stimulus; Stress Fibers; Structure; System; Vascular Diseases; Vascular System; Vascular remodeling; arterial stiffness; base; cadherin 5; constriction; in utero; insight; mouse model; novel; offspring; postnatal; prevent; receptor; restoration; rho; theories

DESCRIPTION (provided by applicant): The concept that adult disease can be influenced by events occurring in utero is based on epidemiological studies demonstrating that infants born 'small for gestational age' (SGA) are at increased risk of developing cardiovascular and metabolic diseases. The theory is supported by animal studies demonstrating that intrauterine growth restriction (IUGR) causes cardiovascular and metabolic disorders. Cellular mechanisms responsible for this phenomenon have not yet been identified. Most IUGR studies have focused on adult consequences of the insult. However, this approach is complicated by indirect effects exerted by the disease processes, which are known to negatively impact vascular function. We have therefore focused on the immediate postnatal period, prior to development of these diseases. The immediate postnatal period is associated with remarkable changes in the structure and function of the endothelium and arterial wall. We demonstrate that the endothelium lining newborn arteries is highly unusual, possessing functional, morphological and signaling characteristics reminiscent of dysfunctional endothelial cells. These include prominent actin stress fibers, poorly organized Adherens Junctions (AJs), impaired eNOS and NO dilator activity, and powerful endothelin-mediated constriction. In the immediate postnatal period, endothelial cells rapidly mature into protective endothelium displaying a cortical actin network, highly-organized AJs, eNOS signaling and exuberant NO activity, and a complete lack of endothelin activity. Endothelial maturation appears to reflect increased signaling at AJs, resulting in a change in endothelial signaling from predominantly Rho/ROCK signaling in newborn endothelium to PI3K/Akt signaling in maturing endothelium. This postnatal maturation process was disrupted in two mouse models of IUGR, with endothelial cells retaining newborn characteristics, including diminished AJ organization and impaired NO activity, present in maturing neonatal arteries. Endothelium of neonatal IUGR arteries also displayed marked expression of angotensin (ANG). Indeed, ANGII inhibition in neonatal arteries completely reversed the pathological endothelial effects of IUGR, including restoration of normal endothelial dilator activity and organization of endothelial AJs. We therefore propose that IUGR disrupts the early postnatal maturation of arterial endothelium resulting in retention of an unusual newborn endothelial phenotype. This disruption appears to be mediated by IUGR-induced local generation of ANGII and activation of endothelial AT1 receptors. We further propose that within the IUGR arterial wall, the local production of ANGII and other components of the immature endothelium will be powerful stimuli for vascular remodeling and cardiovascular diseases associated with IUGR. Three independent and interactive aims will investigate 1) Effects of IUGR on the Postnatal Maturation of Arterial Endothelium, 2) The Role of a Local Angiotensin System in Mediating Endothelial Effects of IUGR, and 3) Disrupted Endothelial Maturation and the Cardiovascular Pathology of IUGR

描述（由申请人提供）：成人疾病可能受到子宫内发生的事件影响的概念基于流行病学研究，该研究表明“小于胎龄”（SGA）出生的婴儿患心血管和代谢疾病的风险增加。该理论得到动物研究的支持，表明宫内生长受限（IUGR）会导致心血管和代谢紊乱。造成这种现象的细胞机制尚未确定。大多数 IUGR 研究都集中于侮辱对成人的后果。然而，这种方法因疾病过程产生的间接影响而变得复杂，已知疾病过程会对血管功能产生负面影响。因此，我们将重点放在这些疾病发生之前的产后时期。出生后不久的时期与内皮和动脉壁的结构和功能的显着变化有关。我们证明，新生动脉的内皮细胞非常不寻常，具有功能、形态和信号传导特征，让人想起功能失调的内皮细胞。这些包括突出的肌动蛋白应力纤维、组织不良的粘附连接 (AJ)、受损的 eNOS 和 NO 扩张剂活性以及强大的内皮素介导的收缩。在出生后不久，内皮细胞迅速成熟为保护性内皮，表现出皮质肌动蛋白网络、高度组织的 AJ、eNOS 信号传导和旺盛的 NO 活性，并且完全缺乏内皮素活性。内皮成熟似乎反映了 AJ 信号传导的增加，导致内皮信号传导从新生内皮中主要的 Rho/ROCK 信号传导转变为成熟内皮中的 PI3K/Akt 信号传导。在两种 IUGR 小鼠模型中，这种出生后成熟过程被破坏，内皮细胞保留了新生儿特征，包括成熟的新生儿动脉中存在的 AJ 组织减少和 NO 活性受损。新生儿 IUGR 动脉内皮也显示出血管紧张素 (ANG) 的显着表达。事实上，新生儿动脉中的 ANGII 抑制完全逆转了 IUGR 的病理内皮效应，包括恢复正常的内皮扩张器活性和内皮 AJ 组织。因此，我们认为 IUGR 破坏了动脉内皮的出生后早期成熟，导致保留了不寻常的新生儿内皮表型。这种破坏似乎是由 IUGR 诱导的 ANGII 局部生成和内皮 AT1 受体激活介导的。我们进一步提出，在 IUGR 动脉壁内，ANGII 和未成熟内皮的其他成分的局部产生将有力地刺激与 IUGR 相关的血管重塑和心血管疾病。将研究三个独立且互动的目标：1) IUGR 对出生后动脉内皮成熟的影响，2) 局部血管紧张素系统在介导 IUGR 内皮效应中的作用，以及 3) IUGR 内皮成熟破坏和心血管病理学