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

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.

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.