ENDOTHELIUM DERIVED VASODILATORS IN PREGNANCY

妊娠期内皮源性血管扩张剂

• 批准号: 6537050
• 负责人: RONALD R MAGNESS
• 金额: $ 28.57万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-07-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6537050
• 关键词: angiogenesis; angiogenesis factor; epidermal growth factor; estrogens; female; fibroblast growth factor; gene expression; hormone regulation /control mechanism; immunocytochemistry; mechanical stress; nitric oxide; nitric oxide synthase; pregnancy; pregnancy circulation; progesterone; prostacyclins; prostaglandin endoperoxide synthase; shear stress; sheep; tissue /cell culture; vascular endothelial growth factors; vascular endothelium; vasodilation; vasodilators; western blottings

Normal cardiovascular adaptations in pregnancy include generalized vasodilatation and reduced uterine and systemic vasoconstrictor responses to infused angiotensin II (ANG II). The specific physiologic, biochemical, and molecular mechanism(s) by which pregnancy alters uterine and systemic flows remain unknown, although it clearly results from both vasodilatation as well as growth/neovascularization. Uteroplacental vasodilation and angiogenesis are associated with increased secretion of basic Fibroblast Growth Factor (bFGF), Epidermal Growth Factor (EGF), and Vascular Endothelial Growth Factor (VEGF) as well as placental derived estrogen and progesterone during the second and third trimesters of pregnancy, at a time when fetal growth and uteroplacental blood flows increase dramatically. This increase in blood flow contributes to dramatic increases in shear stress on the lumenal surface of the vasculature. The uteroplacental vasculature in pregnancy exhibits very prominent production of Nitric Oxide (NO) and Prostacyclin (PGI2) from the endothelium due to increased expression (protein and mRNA) of endothelial NO synthase (eNOS) and cyclooxygenase-1 (COX-1), respectively. The overall hypothesis of this project is that uterine artery endothelium-derived NO and PGI2 productions are increased in normal pregnancy because these vessels are exposed to angiogenic growth factors (e.g. bFGF, EGF, and VEGF), placental steroids (Estrogen and Progesterone), and shear stress. We will examine these specific aims; AIM I Determination of the physiologic factors during the second and third trimester of ovine pregnancy controlling uterine blood flow (UBF) and the in vivo expression of eNOS, COX-1 and PG12 synthase (PGIS) by evaluating the local effects of: (Exp. 1) unilateral uterine arterial infusion of the estrogen receptor antagonist ICI 182780; and (Exp. 2) unilateral reductions in shear stress by occluding UBF. AIM II Determination of the factors which modulate the cellular and molecular (protein and mRNA) expressions of eNOS, COX-1, and PGIS in an established uterine artery endothelial cell (UAEC) culture model derived from pregnant and nonpregnant sheep. We propose to evaluate the effects of the following treatments on NO2/NO3 and PGI2 production as well as the expression of eNOS, COX-1, and PGIS in pregnant and nonpregnant UAEC cultures: (Exp. 1) Angiogenic Growth Factors (bFGF, EGF, and VEGF); (Exp. 2) Estrogen q ICI 182,780 and Progesterone q ZK299 (i.e. q receptor antagonists); (Exp. 3) comparing static cultures vs laminar shear stress and; (Exp. 4) interactions of laminar shear stress and responses to growth factors, estrogen and progesterone. Completion of these studies will provide the framework for understanding the local control of and interactions between growth factors, placental steroids and shear stress on controlling vasodilatation and blood flow to the uteroplacental vasculature. These vasodilatory mechanisms may be reduced in pregnancies complicated by hypertension and/or fetal growth retardation.

妊娠期正常心血管适应包括全身血管舒张以及子宫和全身血管收缩对输注血管紧张素 II (ANG II) 的反应减少。妊娠改变子宫和全身血流的具体生理、生化和分子机制仍然未知，尽管它显然是由血管舒张以及生长/新血管形成引起的。 子宫胎盘血管舒张和血管生成与妊娠中期和晚期碱性成纤维细胞生长因子 (bFGF)、表皮生长因子 (EGF) 和血管内皮生长因子 (VEGF) 以及胎盘源性雌激素和孕激素分泌的增加有关，此时胎儿生长和子宫胎盘血流量急剧增加。 血流量的增加导致脉管系统管腔表面上的剪切应力急剧增加。 由于内皮 NO 合酶 (eNOS) 和环氧合酶-1 (COX-1) 表达（蛋白质和 mRNA）增加，妊娠期子宫胎盘脉管系统表现出非常显着的内皮生成一氧化氮 (NO) 和前列环素 (PGI2)。 该项目的总体假设是，正常妊娠时子宫动脉内皮源性 NO 和 PGI2 的产生增加，因为这些血管暴露于血管生成生长因子（例如 bFGF、EGF 和 VEGF）、胎盘类固醇（雌激素和黄体酮）和剪切应力。 我们将研究这些具体目标；目的 I 通过评估局部效应，确定绵羊妊娠中期和晚期控制子宫血流 (UBF) 的生理因素以及 eNOS、COX-1 和 PG12 合成酶 (PGIS) 的体内表达 (PGIS)：(实验 1) 单侧子宫动脉输注雌激素受体拮抗剂 ICI 182780； （实验 2）通过封闭 UBF 单方面减少剪切应力。 目的 II 确定在已建立的妊娠和非妊娠绵羊子宫动脉内皮细胞 (UAEC) 培养模型中调节 eNOS、COX-1 和 PGIS 的细胞和分子（蛋白质和 mRNA）表达的因素。 我们建议评估以下治疗对妊娠和非妊娠UAEC培养物中NO2/NO3和PGI2产生以及eNOS、COX-1和PGIS表达的影响：（实验1）血管生成生长因子（bFGF、EGF和VEGF）； （实验 2）雌激素 q ICI 182,780 和黄体酮 q ZK299（即 q 受体拮抗剂）； （实验 3）比较静态培养物与层流剪切应力； （实验 4）层流剪切应力与生长因子、雌激素和黄体酮反应的相互作用。这些研究的完成将为了解生长因子、胎盘类固醇和剪切应力之间的局部控制和相互作用对控制血管舒张和流向子宫胎盘脉管系统的血流提供框架。 在妊娠并发高血压和/或胎儿生长迟缓时，这些血管舒张机制可能会减弱。