Long Term Implications of Preeclampsia: Role of Obesity vs sFlt-1 Overexpression

描述（由应用程序提供）：心血管疾病（CVD）是美国女性死亡的主要原因。流行病学研究表明，先兆子痫可以确定妇女在以后的生活中患高血压、冠状动脉疾病、糖尿病和中风的风险增加。然而，先兆子痫不太可能与单一致病因素相关，与CVD具有共同的致病特征，包括内皮功能障碍、血栓形成倾向、胰岛素敏感性改变、高甘油三酯血症和促炎性变化。因此，一些妇女可能有潜在的危险因素，心血管疾病，也容易使他们先兆子痫。肥胖是两者的共同危险因素。C-反应蛋白是炎症的标志物，在这两种情况下都会增加。甚至在先兆子痫临床表现明显之前，血浆瘦素水平就升高了，这表明肥胖基因可能参与其中。最近的报道支持异常血管生成在先兆子痫的发展中的作用。可溶性Flt 1（sFlt 1）是血管内皮生长因子（VEGF）受体1的可溶形式，其结合循环中的VEGF和其他血管生成因子，从而降低它们的作用。基于先前的报道，我们通过用携带sFlt 1的腺病毒感染小鼠成功地表征和改进了先兆子痫的动物模型。该模型的特征在于血压升高，胎盘缺氧，血管，血液学，肝脏和肾脏的变化，在怀孕期间sFlt 1的过度表达。我们还跟踪了这些动物的产后情况。在小鼠分娩后6至8个月进行的初步实验中，我们没有发现注射对照病毒mFc或盐水的小鼠与sFlt 1诱导的先兆子痫小鼠之间的体外血管反应性差异，也没有发现体内血压差异。因此，我们假设妊娠并发症叠加CVD危险因素，如肥胖，导致母体血管系统的长期不良变化。为了验证这一假设，我们提出了以下目标：（1）确定预先存在肥胖的怀孕小鼠的血管功能，有或没有sFlt 1诱导的先兆子痫，并与正常饮食的怀孕小鼠进行比较，有或没有sFlt 1诱导的先兆子痫;以及（2）检测有或没有孕前肥胖以及有或没有sFlt 1诱导的先兆子痫的小鼠的长期心血管血管功能。在该模型中，对妊娠期和产后动物的血管功能进行比较，将阐明预先存在的疾病与先兆子痫的重要性及其在母体CVD发展中的相互作用。该模型还将为研究心血管疾病的机制以及健康和疾病方面的既定性别差异提供实验工具。

DESCRIPTION (provided by application): Cardiovascular disease (CVD) is the leading cause of death in women in the United States. Epidemiological studies have demonstrated that preeclampsia could identify women at increased risk to develop hypertension,coronary artery disease, diabetes, and stroke later in life. However, preeclampsia is unlikely to be associated with a single causative factor and shares common pathogenic features with CVD, including endothelial dysfunction, thrombophilic predisposition, alterations in insulin sensitivity, hypertriglyceridemia, and proinflammatory changes. Therefore, some women may have underlying risk factors for CVD that also predispose them to preeclampsia. Obesity is a common risk factor for both. C-reactive protein, a marker for inflammation, is increased in both conditions. Plasma leptin levels are elevated even before preeclampsia is clinically evident, suggesting that the obese gene may be involved. Recent reports support a role for abnormal angiogenesis in the development of preeclampsia. The soluble Flt1 (sFlt1) is the soluble form of the vascular endothelial growth factor (VEGF) receptor 1, which binds VEGF and other angiogenic factors in the circulation, thereby decreasing their action. Based on prior reports, we successfully characterized and refined an animal model of preeclampsia by transfecting mice with an adenovirus carrying sFlt1. This model is characterized by elevated blood pressure, placental hypoxia, vascular, hematological, hepatic, and renal changes in response to overexpression of sFlt1 during pregnancy. We have also followed these animals postpartum. In preliminary experiments performed in mice 6 to 8 months after delivery, we did not find differences in the vascular reactivity in vitro, nor blood pressure in vivo, between mice injected with control virus mFc or saline and mice that had sFlt1-induced preeclampsia. Therefore, we hypothesize that pregnancy complications superimposed on CVD risk factors, such as obesity, lead to the development of long-term adverse changes in the maternal vasculature. To test this hypothesis, we propose the following aims: (1) to determine vascular function in pregnant mice with preexisting obesity, with or without sFlt1-induced preeclampsia, and compare with that in pregnant mice on a regular diet, with or without sFlt1-induced preeclampsia; and (2) to examine the long-term cardiovascular vascular function in mice with or without pre-pregnancy obesity, and with or without sFlt1- induced preeclampsia. Comparison of vascular function in pregnanct and postpartum animals in this model will shed light on the importance of preexisting conditions versus preeclampsia and their interaction in the development of maternal CVD. This model will also provide an experimental tool for investigating mechanisms of CVD and the well established gender differences in health and disease.