We have utilized an established model of behavioral stress in Dahl salt-sensitive (DS) rats that indicates reactive oxygen species (ROS) mediate the stress-induced increase in blood pressure. We have hypothesized that stress triggers ROS production via mechanisms involving the endothelin (ET) and/or angiotensin II pathways through activation of NADPH oxidase and uncoupled NOS. Project 2's BPStress Cohort of young adults has shown that the response to stress was significantly greater in obese individuals or ones at a lower socioeconomic status that carry a specific ET polymorphism. Data in DS rats indicates that a high fat diet augments the stress-induced blood pressure response when compared to DS rats on a normal fat diet. Given the epidemic of childhood obesity that has contributed to the risk of hypertension, it is important to determine the mechanisms responsible for the augmented stress response. Lower childhood socioeconomic status is recognized to be associated with increased cardiovascular disease morbidity and mortality. We initiated preliminary studies with an established model of early life stress in rats. Pups are separated from their mothers for 3 hr/day from day 2-14 of life. The early life stress (separated) rats display a greater response to stress when compared to the non-separated rats. Rats with an impaired ET signaling pathway that are exposed to early life stress do not have an augmented response to stress in adulthood. These data have led us to predict that early life stress activates a component of the ET pathway that potentiates the stress response. We propose the following specific aims:
Specific Aim 1 : To test the hypothesis that air jet stress activates the ET and/or Ang II pathways, which stimulates NADPH oxidase and/or uncoupled NOS as the enzymatic source of ROS, increasing blood pressure;
Specific Aim 2 : To test the hypothesis that high fat diet augments the air jet stress induced increase in blood pressure via production of ROS;
Specific Aim 3 : To test the hypothesis that early life stress potentiates the air jet stress induced increase in blood pressure via the ET pathway. Relevance: The chronic stressors (high fat diet and early life stress) are models of established stressors that are known to sensitize humans to stress and increase the risk for hypertension. A complete understanding of the mechanisms involved in the blood pressure response to stress may disclose approaches for minimizing the risk of hypertension.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Georgia Regents University
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De Miguel, Carmen; Speed, Joshua S; Kasztan, Malgorzata et al. (2016) Endothelin-1 and the kidney: new perspectives and recent findings. Curr Opin Nephrol Hypertens 25:35-41
Heimlich, J Brett; Speed, Joshua S; O'Connor, Paul M et al. (2016) Endothelin-1 contributes to the progression of renal injury in sickle cell disease via reactive oxygen species. Br J Pharmacol 173:386-95
Davenport, Anthony P; Hyndman, Kelly A; Dhaun, Neeraj et al. (2016) Endothelin. Pharmacol Rev 68:357-418
Gohar, Eman Y; Giachini, Fernanda R; Pollock, David M et al. (2016) Role of the endothelin system in sexual dimorphism in cardiovascular and renal diseases. Life Sci 159:20-9
Spradley, Frank T; Ho, Dao H; Pollock, Jennifer S (2016) Dahl SS rats demonstrate enhanced aortic perivascular adipose tissue-mediated buffering of vasoconstriction through activation of NOS in the endothelium. Am J Physiol Regul Integr Comp Physiol 310:R286-96
Guan, Zhengrong; Singletary, Sean T; Cha, Haword et al. (2016) Pentosan polysulfate preserves renal microvascular P2X1 receptor reactivity and autoregulatory behavior in DOCA-salt hypertensive rats. Am J Physiol Renal Physiol 310:F456-65
Heimlich, J B; Speed, J S; Bloom, C J et al. (2015) ET-1 increases reactive oxygen species following hypoxia and high-salt diet in the mouse glomerulus. Acta Physiol (Oxf) 213:722-30
Su, Shaoyong; Wang, Xiaoling; Pollock, Jennifer S et al. (2015) Adverse childhood experiences and blood pressure trajectories from childhood to young adulthood: the Georgia stress and Heart study. Circulation 131:1674-81
Speed, Joshua S; Fox, Brandon M; Johnston, Jermaine G et al. (2015) Endothelin and renal ion and water transport. Semin Nephrol 35:137-44
Speed, Joshua S; Pollock, David M (2015) New clues towards solving the mystery of endothelin and blood pressure regulation. Hypertension 66:275-7

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