Endothelial Function in a Model of IUGR Induced by Uterine Space Restriction

子宫空间限制引起的 IUGR 模型中的内皮功能

• 批准号: 8786597
• 负责人: RONALD R MAGNESS
• 金额: $ 44.29万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8786597
• 关键词: Address; Adult; Angiogenic Factor; Angiotensin II; Animals; Assisted Reproductive Technology; Attenuated; Barker Hypothesis; Baroreflex; Birth Weight; Blood Pressure; Blood Vessels; Blood Volume; Blood flow; Cardiovascular Diseases; Cardiovascular system; Cells; Clinical; Contracts; Development; Disease; Dyslipidemias; Environment; Essential Hypertension; Exhibits; Exposure to; FGF2 gene; Fetal Growth; Fetal Growth Retardation; Fetus; Fibroblast Growth Factor 2; Gender; Genotype; Growth; Health; Human; Hypertension; In Vitro; Intervention; Kidney; Lead; Life; Maintenance; Maternal-Fetal Exchange; Mediating; Metabolic; Modeling; Molecular; Morbidity - disease rate; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Onset of illness; Outcome; Oxygen; Perfusion; Perinatal Exposure; Phenotype; Physiological; Physiological Processes; Placenta; Placental Insufficiency; Predisposition; Pregnancy; Process; Regulation; Renin; Renin-Angiotensin System; Signal Transduction; Stress; Structural defect; Testing; Therapeutic Intervention; Third Pregnancy Trimester; Vascular Endothelial Growth Factors; Vasodilation; Woman; angiogenesis; base; epidemiologic data; fetal; hypercholesterolemia; in utero; in vivo; male; novel; offspring; postnatal; prevent; programs; response; young adult

DESCRIPTION (provided by applicant): Pregnancy is associated with substantial cardiovascular adaptations including dramatically increased maternal uterine blood flow (UBF) and fetoplacental blood flows for fetal nutrient delivery. Vasodilatation and angiogenesis are the mechanisms normally controlling maternal fetal perfusion, but perfusion is reduced in pregnancies complicated by intrauterine growth restriction (IUGR). Based on the Barker hypothesis, when reaching adulthood, these IUGR/small birth weight babies exhibit a host of adult onset diseases, including hypertension and its associated morbidity. It is of great importance to understand the causes and sequelae of IUGR. Limited uterine space in multi-fetal gestations and uterine anomalies cause IUGR from uterine and placental insufficiency. We developed a novel surgically-created ovine uterine space restriction model that partially maintained UBF with placental vasculature adaptations to sustain viable fetuses with asymmetric IUGR. We propose to utilize this model to study numerous physiological processes involved in placental, fetal, and postnatal vascular development. We will test the hypotheses that during uterine space restriction, both the maternal and fetal components of the placenta (uteroplacental/fetoplacental interface) and specifically their vasculatures initially adapt to preserve sustained fetal growth through partial maintenance of rises in uterine and fetal placental blood flows (Aim I) via NO-mediated vasodilatory (Aim II) as well as VEGF- and FGF2- mediated angiogenesis (Aim III) via cell and molecular signaling mechanisms. However, with growth arrest after 0.9 gestation, both vasodilatory and angiogenic mechanisms are inadequate, leading to placental insufficiency with consequent cessation of fetal growth velocity. Because the vascular adaptations ultimately define the postnatal cardiovascular phenotype of IUGR offspring, we will test the hypothesis that the outcome is postnatal programming of hypertension (Aim IV) with dysfunctional renal development, RAS activation, and altered blood volume and pressor studies in yearling lambs. These aims will address vascular adaptation to decreased uterine space through physiological, signaling, and molecular mechanisms of vasodilatation and angiogenesis.

描述(申请人提供)：怀孕与实质性的心血管适应有关，包括母体子宫血流量(UBF)和胎儿胎盘血流量的急剧增加，以满足胎儿营养的需要。血管扩张和血管生成通常是控制母体胎儿血流灌注的机制，但在妊娠合并宫内生长受限(IUGR)时，血流灌注量会减少。根据巴克假说，当这些IUGR/出生体重小的婴儿成年后，会表现出一系列成人发病的疾病，包括高血压及其相关的发病率。了解胎儿宫内发育迟缓的原因及后遗症具有重要意义。多胎妊娠中子宫空间有限和子宫异常导致子宫和胎盘功能不全引起的IUGR。我们开发了一种新的手术建立的绵羊子宫空间限制模型，该模型部分维持了UBF，并进行了胎盘血管的适应，以支持患有不对称性IUGR的存活胎儿。我们建议利用这个模型来研究涉及胎盘、胎儿和出生后血管发育的众多生理过程。我们将验证这样的假设：在子宫空间受限期间，胎盘的母体和胎儿组件(子宫胎盘/胎儿胎盘界面)以及它们的血管最初都通过细胞和分子信号机制部分维持子宫和胎儿胎盘血流量的上升(AIM I)，通过NO介导的血管扩张(AIM II)以及血管内皮生长因子和FGF2介导的血管生成(AIM III)来维持胎儿的持续生长。然而，随着0.9孕龄后生长停止，血管扩张和血管生成机制都不充分，导致胎盘功能不全，从而导致胎儿生长速度停止。由于血管适应最终决定了IUGR后代出生后的心血管表型，我们将检验这一假设，即结果是出生后高血压(Aim IV)的结果是肾脏发育障碍、RAS激活以及一岁羔羊血液容量和升压研究的改变。这些目标将通过血管扩张和血管生成的生理、信号和分子机制来解决血管对子宫空间缩小的适应。