Impaired Endothelial Maturation and the Developmental Origin of Vascular Disease

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是基于流行病学研究，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。这一理论得到了动物研究的支持，这些研究表明宫内生长受限（IUGR）会导致心血管和代谢紊乱。负责这种现象的细胞机制尚未确定。大多数IUGR研究都集中在侮辱的成年后果上。然而，这种方法由于疾病过程产生的间接影响而变得复杂，已知这些间接影响会对血管功能产生负面影响。因此，我们把重点放在这些疾病发展之前的产后时期。出生后即刻与内皮和动脉壁的结构和功能的显著变化有关。我们证明，新生儿动脉内皮内衬是非常不寻常的，具有功能，形态和信号特征，让人想起功能障碍的内皮细胞。这些包括突出的肌动蛋白应力纤维，组织不良的粘附连接（AJs），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，显示皮质肌动蛋白网络、高度组织化的AJs、eNOS信号传导和旺盛的NO活性，以及完全缺乏内皮素活性。内皮成熟似乎反映了AJs处的信号传导增加，导致内皮信号传导从新生内皮中的主要Rho/ROCK信号传导改变为成熟内皮中的PI 3 K/Akt信号传导。这出生后的成熟过程中被破坏的IUGR的两个小鼠模型，与内皮细胞保留新生儿的特征，包括减少AJ组织和受损的NO活性，存在于成熟的新生儿动脉。IUGR新生儿血管内皮细胞也有明显的血管紧张素（ANG）表达。事实上，新生儿动脉中的ANGII抑制完全逆转了IUGR的病理性内皮效应，包括恢复正常的内皮扩张活性和内皮AJs的组织化。因此，我们认为IUGR破坏了出生后早期动脉内皮的成熟，导致保留了一种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AT 1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组分的局部产生将是与IUGR相关的血管重塑和心血管疾病的有力刺激。三个独立和相互作用的目标将调查1）IUGR对出生后动脉内皮细胞成熟的影响，2）局部血管紧张素系统在介导IUGR内皮效应中的作用，3）IUGR的内皮细胞成熟中断和心血管病理学

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