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

先兆子痫的长期影响：肥胖与 sFlt-1 过度表达的作用

• 批准号: 7813371
• 负责人: Egle Bytautiene Prewit
• 金额: $ 5.58万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-19 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7813371
• 关键词: Adenoviruses; Affect; Angiogenic Factor; Animal Model; Animals; Binding; Blood; Blood Circulation; Blood Pressure; Blood Vessels; C-reactive protein; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cholesterol; Clinical; Conscious; Coronary Arteriosclerosis; Coronary heart disease; Data; Development; Diabetes Mellitus; Diet; Disease; Edema; Elderly; Environmental Risk Factor; Epidemiologic Studies; Etiology; Fatty acid glycerol esters; Functional disorder; Future; Genes; Genetic; Glucose; Goals; Health; Hepatic; Histopathology; Human; Hyperglycemia; Hyperinsulinism; Hyperlipidemia; Hypertension; Hypertriglyceridemia; Hypoxia; Impairment; In Vitro; Incidence; Insulin Resistance; Intervention; Investigation; Kidney; Lead; Leptin; Life; Light; Link; Liver Dysfunction; Measurement; Measures; Mediating; Modeling; Morbidity - disease rate; Mothers; Mus; Obesity; Organ; Outcome; Overweight; Pathway interactions; Patients; Placentation; Plasma; Postpartum Period; Pre-Eclampsia; Predisposition; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pregnant Women; Prevention strategy; Proteinuria; Rattus; Recording of previous events; Relative (related person); Reporting; Reproduction; Risk; Risk Factors; Role; Saline; Screening procedure; Severities; Sex Characteristics; Stroke; Symptoms; Syndrome; Telemetry; Testing; Time; Transducers; Transfection; Triglycerides; United States; Vascular Diseases; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents; Virus; Woman; angiogenesis; base; cardiovascular disorder risk; cardiovascular risk factor; cohort; in vivo; inflammatory marker; insulin sensitivity; mortality; mouse model; normotensive; novel; offspring; overexpression; pregnant; prevent; prospective; research study; response; tool; trophoblast; vasoactive agent

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.

描述（由申请表提供）：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，先兆子痫可以确定女性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的致病因素相关，并且与CVD具有共同的致病特征，包括内皮功能障碍、嗜血栓易感性、胰岛素敏感性改变、高甘油三酯血症和促炎改变。因此，一些女性可能有潜在的心血管疾病风险因素，也使她们易患子痫前期。肥胖是这两种疾病的常见危险因素。c反应蛋白（炎症的标志）在两种情况下都有所增加。血浆瘦素水平升高甚至在子痫前期临床表现明显之前，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子痫前期发展中的作用。可溶性Flt1 （sFlt1）是血管内皮生长因子（VEGF）受体1的可溶性形式，与血管内皮生长因子（VEGF）和其他血管生成因子在循环中结合，从而降低其作用。基于先前的报道，我们通过转染携带sFlt1的腺病毒成功地表征和完善了子痫前期动物模型。该模型的特点是妊娠期间sFlt1过表达导致血压升高、胎盘缺氧、血管、血液学、肝脏和肾脏发生变化。我们还跟踪了这些动物的产后情况。在分娩后6至8个月的小鼠中进行的初步实验中，我们没有发现注射对照病毒mFc或生理盐水的小鼠和sflt1诱导的子痫前期小鼠在体外血管反应性和体内血压方面存在差异。因此，我们假设妊娠并发症叠加心血管疾病危险因素，如肥胖，导致母体血管系统发生长期不良变化。为了验证这一假设，我们提出了以下目的：(1)测定患有或不患有sflt1诱导的子痫前期肥胖的妊娠小鼠的血管功能，并与正常饮食的妊娠小鼠的血管功能进行比较，无论是否患有sflt1诱导的子痫前期；(2)观察有无孕前肥胖、有无sFlt1诱导的子痫前期小鼠的长期心血管功能。在该模型中，比较妊娠和产后动物的血管功能将揭示先兆子痫和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中已确立的性别差异提供实验工具。