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

描述（由申请人提供）：非裔美国人外周血管和内皮功能受损，这可能是他们高血压患病率高的原因。高血压是多种遗传和环境因素相互作用的结果。有氧运动训练（ExTr）通过诱导内皮细胞（EC）因反复暴露于血管剪切应力升高而适应，从而纠正内皮功能障碍。然而，在非裔美国人中，运动训练对内皮功能的影响和EC基因对层流剪切应力（LSS）（一种体外运动模型）的表达反应都不为人所知。生理上高水平的LSS，如有氧运动中出现的LSS，会引起EC基因表达，与较低的血压（BP）一致。功能基因群中单核苷酸多态性（snp）的组合可以解释静息血压的变异性和ExTr血压变化的变异性。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/抗氧化系统，3)剪切应激信号系统。假设：三个EC功能群基因中先天选择的功能性snp将有助于外周血管功能和基线血压，并解释非洲裔美国高血压患者对有氧运动训练的反应，这些功能性snp将与从非洲裔美国人获得并暴露于LSS的人脐静脉细胞（HUVECs）中的差异基因表达有关。具体目标是：1)确定三个EC功能组中剪切应力调节基因内的功能snp是否与剪切应力/血流介导的舒张（FMD）、前臂绝对血流（FBFA）以及随机和24小时动态血压的变化有关。2)从非洲裔美国人获得的基因型培养HUVECs在Specific Aim 1中具有相同的功能snp。将其暴露于与有氧运动时达到的体内水平相当的LSS中，然后进行基因表达谱分析和RT-PCR，以确定基因表达是否存在基因型依赖性差异。3)进行SNP发现。将标准化扰动应用于外周血管和内皮细胞，将使我们能够检测遗传效应，从而深入了解高血压外周血管的分子生物学机制。

DESCRIPTION (provided by applicant): 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.