Maternal Endothelial Progenitor Cells and Preeclampsia

母体内皮祖细胞和先兆子痫

• 批准号: 6902976
• 负责人: Carl A Hubel
• 金额: $ 15.21万
• 依托单位: MAGEE-WOMEN'S RES INST AND FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6902976
• 关键词: biological models; cell biology; clinical research; estradiol; female; flow cytometry; gene delivery system; growth factor; hormone regulation /control mechanism; human pregnant subject; human subject; laboratory mouse; model design /development; pathologic process; patient oriented research; postpartum; preeclampsia; pregnancy circulation; protein engineering; stem cells; tissue /cell culture; transfection; vascular endothelial growth factors; vascular endothelium; women' s health

DESCRIPTION (provided by applicant): There is compelling evidence that adaptive changes in the maternal vascular endothelium are important for normal pregnancy and that endothelial dysfunction contributes to the pathogenesis of preeclampsia. The reasons for these changes, however, are not fully understood. Endothelial health/dysfunction ultimately represents a balance between factors that promote injury and the capacity for repair. It has long been thought that repair of the endothelium in the adult occurred solely by adjacent (local) endothelial cell replication, migration, and replacement. New data, however, have demonstrated the presence of endothelial progenitor (precursor) cells (EPCs) that are mobilized from the adult bone marrow into the peripheral circulation upon appropriate stimuli. These cells have the capacity to proliferate, migrate, and differentiate into endothelial cells lining the lumen of blood vessels postnatally. Risk factor-induced dysfunction of EPCs is now thought to contribute to the progression of cardiovascular disease. The long-range hypothesis of the proposed pilot study is that increased mobilization and activity of adult bone marrow-derived EPCs is important for normal pregnancy and that functional impairment of EPCs contributes to development of preeclampsia. Accordingly, Aim la is to test whether the number of EPCs in peripheral blood, and functional activity of EPCs in vitro (survival/proliferation, migration, and integration into vascular structures), increases with pregnancy in the human, correlating with plasma concentrations of estradiol and (free) VEGF and placental growth factor (P1GF). Aim 1b is to engineer two fluorescent proteins for tagging endothelial-lineage stem cells in mice using a retroviral vector-based gene delivery technique, and, as an initial experiment, to use these markers to demonstrate that EPCs integrate into the maternal microvasculature. Aim 2 is to compare women with normal and preeclamptic pregnancies regarding EPC number and function, and to ask if these variables correlate inversely with plasma concentrations of the soluble receptor sFlt-1, an anti-angiogenic circulating antagonist of P1GF and VEGF that is increased in plasma of women with preeclampsia. Building upon data that both cardiovascular morbidity and mortality and cardiovascular risk factors are elevated in women with a history of preeclampsia, Aim 3 is to compare EPCs and plasma factors in women with prior preeclampsia and prior normal pregnancy, 6 to 24 months postpartum. As EPC function is modifiable, this systematic, groundbreaking study could provide clues to prevention or treatment of preeclampsia and associated later-life cardiovascular disease.

描述（由申请人提供）：有令人信服的证据表明，母体血管内皮的适应性变化对正常妊娠很重要，内皮功能障碍有助于先兆子痫的发病机制。然而，这些变化的原因并不完全清楚。内皮健康/功能障碍最终代表促进损伤的因素与修复能力之间的平衡。长期以来，人们一直认为成人内皮细胞的修复仅通过邻近（局部）内皮细胞的复制、迁移和替换来发生。然而，新的数据表明，内皮祖细胞（前体）细胞（EPCs）的存在下，动员从成人骨髓进入外周循环后，适当的刺激。这些细胞具有增殖、迁移和分化为血管内皮细胞的能力。危险因素诱导的EPCs功能障碍现在被认为有助于心血管疾病的进展。所提出的初步研究的长期假设是，成人骨髓来源的EPCs的动员和活性增加对正常妊娠很重要，EPCs的功能障碍有助于先兆子痫的发生。因此，目的1a是测试外周血中EPC的数量和体外EPC的功能活性（存活/增殖、迁移和整合到血管结构中）是否随着人的妊娠而增加，与雌二醇和（游离）VEGF和胎盘生长因子（PlGF）的血浆浓度相关。目的1b是使用基于逆转录病毒载体的基因递送技术，设计两种荧光蛋白用于标记小鼠中的内皮谱系干细胞，并且作为初始实验，使用这些标记物来证明EPCs整合到母体微血管中。目的2是比较正常和先兆子痫妊娠妇女的EPC数量和功能，并询问这些变量是否与可溶性受体sFlt-1（一种P1 GF和VEGF的抗血管生成循环拮抗剂，在先兆子痫妇女的血浆中增加）的血浆浓度呈负相关。在有先兆子痫病史的妇女心血管发病率和死亡率以及心血管危险因素升高的数据基础上，目的3是比较先兆子痫妇女和正常妊娠妇女产后6至24个月的EPCs和血浆因子。由于EPC的功能是可以改变的，这项系统的，开创性的研究可以为预防或治疗先兆子痫和相关的晚年心血管疾病提供线索。