Impaired Endothelial Maturation and the Developmental Origin of Vascular Disease

描述(由申请人提供)：成人疾病可能受子宫内发生的事件影响的概念是基于流行病学研究表明，出生时小于胎龄(SGA)的婴儿患心血管和代谢性疾病的风险增加。这一理论得到了动物研究的支持，该研究表明，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研究都集中在这种侮辱对成年人的影响上。然而，这种方法因疾病过程所产生的间接影响而变得复杂，众所周知，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生之前的出生后即刻。出生后即刻，血管内皮细胞和动脉壁的结构和功能发生显著变化。我们证明，新生动脉内皮细胞是非常不寻常的，具有功能、形态和信号特征，使人联想到功能失调的内皮细胞。这些包括突出的肌动蛋白应激纤维，组织不良的粘连连接(AJ)，eNOS受损和没有扩张器活性，以及强大的内皮素介导的收缩。在出生后即刻，内皮细胞迅速成熟为保护性内皮细胞，表现为皮质肌动蛋白网络、高度组织化的AJ、eNOS信号和旺盛的NO活性，以及完全缺乏内皮素活性。内皮成熟似乎反映了AJs信号的增加，导致内皮信号从新生内皮中主要的Rho/ROCK信号转变为成熟内皮中的PI3K/Akt信号。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的特征，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IUGR动脉内皮细胞也有明显的Angotensin(Ang)表达。事实上，抑制新生动脉中的血管紧张素Ⅱ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的组织。因此，我们认为IUGR破坏了出生后动脉内皮细胞的早期成熟，导致了一种不寻常的新生内皮表型的保留。这种破坏似乎是由IUGR诱导的局部血管紧张素Ⅱ生成和内皮AT1受体的激活所介导的。我们进一步认为，在IUGR动脉壁内，局部产生的AngII和其他成分的未成熟内皮细胞将是与IUGR相关的血管重构和心血管疾病的强大刺激因素。三个独立和相互作用的目标将研究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，以及3)IUGR内皮成熟障碍和心血管病理

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