Maternal Endothelial Progenitor Cells and Preeclampsia

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子痫前期的发病机制。然而，这些变化的原因尚不完全清楚。内皮健康/功能障碍最终代表了促进损伤因素和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、迁移和替换发生。然而，新的数据表明，内皮祖细胞（前体细胞）的存在，在适当的刺激下从成人骨髓被动员到外周循环中。这些细胞在出生后具有增殖、迁移和分化为血管腔内内皮细胞的能力。危险因素诱导的内皮祖细胞功能障碍现在被认为有助于心血管疾病的进展。该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的功能损害有助于子痫前期的发展。因此，Aim la旨在检测外周血中EPCs的数量以及体外EPCs的功能活性（存活/增殖、迁移和整合到血管结构中）是否随着妊娠而增加，并与血浆雌二醇、（游离）VEGF和胎盘生长因子（P1GF）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，设计两种荧光蛋白用于标记小鼠内皮系干细胞，并作为初始实验，使用这些标记物来证明EPCs整合到母体微血管中。目的2是比较正常妊娠妇女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可溶性受体sFlt-1的血浆浓度呈负相关，sFlt-1是一种P1GF和VEGF的抗血管生成循环拮抗剂，在子痫前期妇女的血浆中升高。基于有子痫前期病史的妇女心血管发病率、死亡率和心血管危险因素升高的数据，目的3是比较产后6至24个月有子痫前期和正常妊娠的妇女的EPCs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子痫前期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.