Pregnancy, Pre-eclampsia, Anti-oxidants Endothelial Cell

描述(申请人提供)：目前对子痫前期病因学的一个假说是内皮功能障碍继发于氧化应激，一些临床研究表明预防性应用抗氧化剂可能对预防它有用。目前，NICHD的母婴网络正在进行一项利用抗氧化剂维生素C和维生素E的更大规模的试验，以评估它们在预防先兆子痫方面的有效性。血管内皮细胞的激活通常伴随着这种情况。内皮细胞激活导致内皮细胞功能障碍，同时伴随着黏附分子的表达，即血管细胞黏附分子-1(VCAM-1)等黏附分子的表达。这导致单核细胞与内皮细胞的黏附，类似于早期动脉粥样硬化的形成。有证据表明，肿瘤坏死因子a(TNFa)可由胎盘和激活的白细胞释放，导致内皮细胞的激活。目前的建议将主要集中在雌激素和抗氧化剂阻止TNFa诱导的内皮细胞激活和凋亡的机制。因此，我们将检验以下四个假设。假设1：内皮细胞暴露于TNFa后，最初导致细胞激活，导致VCAM-1表达和抗凋亡蛋白合成增加，随后刺激生存途径。假设2：尽管NFkB没有迁移到细胞核，但雌激素及其代谢产物通过增加eNOS的表达和Akt和ERK1/2的磷酸化来阻止TNFa诱导的HUVEC的激活和凋亡，从而将细胞引导到“生存路径”。假设3：抗氧化剂通过NO独立的Fak介导机制阻止内皮细胞活化，并抑制内皮细胞暴露于TNFa后NFkB向细胞核的迁移。假设4：抗氧化剂通过上调ERK1/2的磷酸化和下调p38的磷酸化来减轻暴露于TNFa的内皮细胞的凋亡。这些研究的结果也将有助于解释雌激素和抗氧化剂阻止内皮细胞激活和细胞凋亡的不同机制(S)，从而为女性服用抗氧化剂预防有这种疾病风险的女性先兆子痫奠定科学基础。先兆子痫是一种在怀孕期间突然发展起来的疾病，并伴随着高血压、身体肿胀和蛋白质泄漏。这种情况可能对母亲和胎儿都有不利影响。先兆子痫在非裔美国人中更为普遍，在较低的社会经济群体中也很常见。我们的研究结果将告诉我们，哪些抗氧化剂可能比其他抗氧化剂更有效，哪些可以用于临床预防这种情况。

DESCRIPTION (provided by applicant): A current hypothesis for the etiology of pre-eclampsia is that endothelial dysfunction is secondary to oxidative stress and some clinical studies have indicated that prophylactic administration of anti-oxidants may be useful in its prevention. A much larger trial utilizing the anti-oxidants vitamin C and vitamin E is, at present, being carried out by the Maternal-Fetal Network of the NICHD to assess their effectiveness in the prevention of pre-eclampsia. Endothelial cell activation is usually a constant accompaniment with this condition. Endothelial cell activation leads to endothelial cell dysfunction and is also accompanied by expression of adhesion molecules, i.e. vascular cell adhesion molecule-1 (VCAM-1), and other adhesion molecules. This leads to adhesion of monocytes to endothelial cells resembling early atherogenesis. There is evidence in the literature that tumor necrosis factor a (TNFa) may be released by the placenta and activated leukocytes leading to activation of endothelial cells. The current proposal will mainly focus on mechanisms by which estrogens and anti-oxidants prevent TNFa-induced endothelial cell activation and apoptosis. We will, therefore, test the following four hypotheses. Hypothesis 1: Exposure of endothelial cells to TNFa leads, initially, to activation of the cells leading to VCAM-1 expression and increased synthesis of anti-apoptotic proteins, followed by stimulation of the survival pathway. Hypothesis 2: Estrogen and its metabolites prevent TNFa-induced activation, as well as apoptosis of HUVEC, by increasing the expression of eNOS and phosphorylation of Akt and ERK 1/2, in spite of the absence of migration of NFkB to the nucleus, thereby, directing the cells to the "survival pathway". Hypothesis 3: Anti-oxidants prevent endothelial cell activation and inhibit NFkB migration to the nucleus following exposure of endothelial cells to TNFa by an NO-independent Fak-mediated mechanism. Hypothesis 4: Anti-oxidants attenuate apoptosis in endothelial cells exposed to TNFa by upregulation of ERK 1/2 phosphorylation and downregulation of p38 phosphorylation. Results from these studies will also help explain the different mechanism(s) by which estrogens and anti-oxidants prevent activation of endothelial cells and apoptosis and, thereby, lay the scientific foundation by which anti-oxidants administered to women may prevent pre- eclampsia in women at risk of developing this condition. Pre-eclampsia is a condition that suddenly develops during pregnancy and is accompanied by high blood pressure, swelling of the body, and leakage of proteins. This condition can adversely affect both the mother and the fetus. Pre-eclampsia is more prevalent in Afro-Americans and is also seen in the lower socio-economic groups. Results from our studies will indicate to us which anti-oxidants are likely to be more effective than others and which can be used clinically to prevent this condition.