Maternal Endothelial Progenitor Cells and Preeclampsia

描述(申请人提供)：有令人信服的证据表明，母体血管内皮细胞的适应性变化对正常妊娠非常重要，内皮功能障碍有助于先兆子痫的发病。然而，这些变化的原因还没有完全被理解。内皮健康/功能障碍最终代表了促进损伤的因素和修复能力之间的平衡。长期以来，人们一直认为成人的内皮修复完全是通过邻近(局部)内皮细胞的复制、迁移和替换来实现的。然而，新的数据表明，在适当的刺激下，内皮祖(前体)细胞(EPC)的存在从成人骨髓动员到外周循环中。这些细胞在出生后具有增殖、迁移和分化为血管管腔内皮细胞的能力。危险因素诱导的内皮祖细胞功能障碍现在被认为是心血管疾病进展的原因之一。拟议的初步研究的长期假设是，增加成人骨髓来源的内皮祖细胞的动员和活性对正常妊娠非常重要，内皮祖细胞的功能障碍有助于先兆子痫的发生。因此，研究的目的是测试外周血中内皮祖细胞的数量以及体外内皮祖细胞的功能活性(存活/增殖、迁移和整合到血管结构中)是否随着妊娠的增加而增加，与血浆雌二醇、(游离)血管内皮生长因子和胎盘生长因子(P1GF)的浓度相关。目的1b是利用基于逆转录病毒载体的基因传递技术设计两种用于标记小鼠内皮细胞系干细胞的荧光蛋白，并作为初步实验，使用这些标记来证明内皮祖细胞整合到母体微血管系统中。目的2是比较正常妊娠和子痫前期妊娠妇女的EPC数量和功能，并询问这些变量是否与血浆可溶性受体sFlt-1浓度呈负相关，sFlt-1是一种抗血管生成循环拮抗剂，P1GF和VEGF在子痫前期妇女血浆中升高。根据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均升高的数据，目标3是比较有先兆子痫史的妇女和有过正常妊娠史的妇女在产后6至24个月内的内皮祖细胞和血浆因子。由于EPC功能是可改变的，这项系统的、开创性的研究可能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。

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.