Genetics of In Vivo and In Vitro Endothelial Function in African Americans

非裔美国人的外周血管和内皮功能受损，可能是导致 他们高血压的高患病率。高血压是由以下因素的独立和交互作用造成的 多种遗传和环境因素。有氧运动训练(EXCR)纠正内皮功能障碍 通过诱导内皮细胞(EC)因反复暴露于升高的血管切变而产生适应 压力。然而，运动训练对血管内皮细胞功能和EC基因表达的影响 对层流剪应力(LSS)的反应，一种体外运动模型，在非裔美国人中是已知的。高 生理水平的LSS，例如在有氧运动中出现的LSS，会诱导EC基因表达，从而 与较低的血压(BP)相一致。中国人群中的单核苷酸多态(SNPs)组合 功能基因群可能解释了静息BP的大部分变异性和 随Extr的变化。我们将重点介绍EC基因的三个功能群：1)血管活性系统，2) 氧化/抗氧化剂系统；3)切应力信号系统。假设：功能SNPs，选定 先验和定位于三个EC功能基团中的基因将有助于外周血管功能 和BP，并解释他们对非裔美国人有氧运动训练的反应 这些功能SNPs可能与人类差异基因表达有关 取自非裔美国人的脐带静脉细胞(HUVECs)，暴露于LSS。具体目标是 目的：1)确定三种EC中剪应力调节基因内的功能性SNPs是否具有功能性 组与切应力/血流介导的扩张(FMD)、绝对前臂血液的变化有关 2)培养人脐静脉内皮细胞(HUVECs)的血流量(FBFA)，以及随ExtR的变化 从非洲裔美国人那里获得的在特定目标1中具有相同功能的SNP，将他们暴露在LSS 在有氧运动中达到的体内水平相当，然后进行基因表达 分析和RT-PCR以确定基因表达是否存在依赖于基因型的差异，3) 进行SNP发现。标准化扰动在外周血管系统中的应用 ECS，将使我们能够检测到基因效应，这将为我们对分子生物学外围设备提供洞察 高血压的血管机制。

Peripheral vasculature and endothelial function are impaired in African Americans and likely contribute to their high prevalence of hypertension. Hypertension results from the independent and interactive effects of multiple genetic and environmental factors. Aerobic exercise training (ExTr) corrects endothelial dysfunction by eliciting adaptations in endothelial cells (EC) due to their repeated exposure to elevated vascular shear stress. However, neither the effects of exercise training on endothelial function nor the EC gene expression response to laminar shear stress (LSS), an in vitro model of exercise, are known in African Americans. High physiological levels of LSS, such as those that occur during aerobic exercise, elicit EC gene expression that is consistent with lower blood pressure (BP). Combinations of single nucleotide polymorphisms (SNPs) in functional genes groups may explain a large portion of the variability in resting BP and in the variability of the changes in BP with ExTr. We will focus on three EC gene functional groups: 1) vasoactive system, 2) oxidant/antioxidant system, and 3) the shear stress signaling system. Hypothesis: functional SNPs, selected apriori and located in genes in the three EC functional groups will contribute to peripheral vascular function and BP at baseline and explain their responses to aerobic exercise training in African American hypertensives, and that these functional SNPs will be related to differential gene expression in human umbilical vein cells (HUVECs) obtained from African Americans and exposed to LSS. The Specific Aims are to: 1) Determine whether functional SNPs within shear stress-regulated genes in the three EC functional groups are associated with changes in shear stress/flow-mediated dilation (FMD), absolute forearm blood flow (FBFA), and changes in casual and 24-hour ambulatory BP with ExTr, 2) Genotype cultured HUVECs obtained from African Americans for the same functional SNPs in Specific Aim 1, expose them to LSS at levels comparable to in vivo levels achieved during aerobic exercise and then perform gene expression profiling and RT-PCR to determine if there are genotype-dependent differences in gene expression, 3) conduct SNP discovery. The application of a standardized perturbation to the peripheral vasculature and ECs, will enable us to detect genetic effects that will provide insights into the molecular biological peripheral vascular mechanisms of hypertension.