Impaired Endothelial Maturation and the Developmental Origin of Vascular Disease

描述（由申请人提供）：子宫内发生的事件可能影响成人疾病的概念是基于流行病学研究，这些研究表明，出生时“小于胎龄”（SGA）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，宫内生长限制（IUGR）会导致心血管和代谢紊乱。造成这一现象的细胞机制尚未被确定。大多数IUGR研究都集中在侮辱对成人的影响上。然而，这种方法由于疾病过程施加的间接影响而变得复杂，这些影响已知会对血管功能产生负面影响。因此，我们把重点放在发生这些疾病之前的紧接的产后时期。出生后不久，内皮和动脉壁的结构和功能发生了显著变化。我们证明新生动脉内膜是非常不寻常的，具有功能、形态和信号特征，使人想起功能失调的内皮细胞。这些包括突出的肌动蛋白应激纤维，组织不良的粘附连接（AJs），受损的eNOS和NO扩张活性，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，表现为皮质肌动蛋白网络、高度组织的AJs、eNOS信号和旺盛的NO活性，而内皮素活性完全缺乏。内皮成熟似乎反映了AJs信号的增加，导致内皮信号从新生内皮的主要Rho/ROCK信号转变为成熟内皮的PI3K/Akt信号。在两种IUGR小鼠模型中，这种产后成熟过程被破坏，内皮细胞保留了新生儿的特征，包括成熟的新生儿动脉中AJ组织减少和NO活性受损。新生儿IUGR动脉内皮也有明显的血管紧张素（angotensin， ANG）表达。事实上，新生儿动脉中ANGII的抑制完全逆转了IUGR的病理内皮效应，包括恢复正常的内皮扩张活性和内皮AJs的组织。因此，我们认为IUGR破坏了出生后动脉内皮的早期成熟，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的局部生成和内皮AT1受体的激活介导的。我们进一步提出，在IUGR动脉壁内，局部产生的ANGII和其他未成熟内皮成分将有力地刺激血管重构和与IUGR相关的心血管疾病。三个独立且相互作用的目标将研究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IUGR介导内皮效应中的作用，以及3)内皮成熟中断和IUGR的心血管病理

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