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于正常妊娠很重要，并且内皮功能障碍有助于先兆子痫的发病机理。但是，这些变化的原因尚未完全理解。内皮健康/功能障碍最终代表了促进伤害和维修能力的因素之间的平衡。长期以来，人们一直认为，成人内皮的修复仅是仅通过相邻（局部）内皮细胞复制，迁移和替换而发生的。然而，新数据证明了存在适当刺激后从成年骨髓动员到周围循环的内皮祖细胞（EPC）的存在。这些细胞在产后在血管内衬里，迁移和区分到血管内皮的内皮细胞中。危险因素引起的EPC功能障碍现在被认为有助于心血管疾病的发展。拟议的试点研究的远程假设是，成人骨髓衍生的EPC的动员和活性增加对于正常妊娠很重要，而EPC的功能障碍有助于前倾斜的发展。因此，目标是测试EPC在体外的EPC数量以及EPC在体外的功能活性（生存/增殖，迁移和整合到血管结构中），与人类妊娠的增加，与血浆雌二醇和雌二醇的血浆浓度与雌二醇和（自由）VEGGF和（自由）veggf和胎盘生长因子（P1GF）相关。 AIM 1B是使用基于逆转录病毒载体的基因递送技术来设计两种荧光蛋白，以在小鼠中对内皮细胞进行标记，并作为初步实验，用于使用这些标记来证明EPCS将EPCS整合到母体微腔中。目的2是要比较有关EPC数量和功能正常和先兆妊娠的妇女，并询问这些变量是否与可溶性受体SFLT-1的血浆浓度成反比，这是P1GF和VEGF的抗血管生成循环拮抗剂的P1GF和VEGF，而妇女在患有前偏抑制前层的女性中会增加。基于患有前启示性的史的女性，基于心血管发病率和死亡率以及心血管危险因素的数据，AIM 3是比较先前的前脱位和事先怀孕的女性的EPC和血浆因素，产后6至24个月。由于EPC功能是可修改的，因此这项系统的，开创性的研究可以为预防或治疗先兆子痫和相关后期生活的心血管疾病提供线索。