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: 7689212
• 负责人: Egle Bytautiene Prewit
• 金额: $ 7.55万
• 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 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7689212
• 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，先兆子痫可以识别出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，而是与CVD有共同的致病特征，包括内皮功能障碍、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危险因素，这也是她们易患先兆子痫的原因。肥胖是这两种疾病的共同风险因素。C反应蛋白是炎症的标志，在这两种情况下都会增加。血浆瘦素水平甚至在子痫前期临床表现明显之前就已经升高，这表明肥胖基因可能参与了这一过程。最近的报道支持异常血管生成在子痫前期的发展中所起的作用。可溶性Flt1(SFlt1)是血管内皮生长因子受体1的可溶性形式，它与循环中的血管内皮生长因子和其他血管生成因子结合，从而降低它们的作用。基于先前的报道，我们通过将携带sFlt1的腺病毒感染小鼠，成功地表征和改进了一种先兆子痫的动物模型。该模型的特点是血压升高，胎盘缺氧，血管，血液，肝脏和肾脏的变化，以回应sFlt1在怀孕期间的过度表达。我们也对这些动物进行了产后跟踪。在分娩后6至8个月在小鼠身上进行的初步实验中，我们没有发现注射对照病毒MFC或生理盐水的小鼠与sFlt1诱导的先兆子痫小鼠在体外血管反应性和体内血压方面的差异。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，会导致母体血管的长期不利变化。为了验证这一假设，我们提出了以下目标：(1)检测有或没有sFlt1诱导的子痫前期的肥胖孕鼠的血管功能，并与有或不有sFlt1诱导的子痫前期的常规饮食孕鼠的血管功能进行比较；(2)检测有或没有孕前肥胖以及有或不有sFlt1诱导的子痫前期的小鼠的长期心血管血管功能。在这个模型中，比较孕期和产后动物的血管功能，将有助于阐明先兆疾病和先兆子痫的重要性，以及它们在母体心血管疾病发展中的相互作用。这一模型还将为研究心血管疾病的机制以及健康和疾病方面公认的性别差异提供一个实验工具。