It has been become increasingly clear that T lymphocytes play an important role in the pathophysiology of hypertension and more recently in psychological stress and depression related disabilities. Given that chronic psychological stress is also a key contributing factor to the development and maintenance of hypertension, further understanding of the adaptive immune response and the underlying neuroimmune mechanism(s) is warranted. The central nervous system (CNS) plays an essential role in the regulation of blood pressure and has long been known to have bi-directional communication with the immune system. Recently our group has shown that the CNS, in particular the anteroventral third ventricle (AV3V) forebrain region, is critical for the development of peripheral vascular inflammation and T cell activation during angiotensin II-induced hypertension. The results of these studies reveal a new understanding for the link between central signals, peripheral inflammation and hypertension. In the proposed studies we plan to investigate the role of the adaptive immune response in stress-induced hypertension and to further characterize the underlying neurocircuitry. The bed nucleus of the stria terminalis (BNST) is a rostral forebrain structure that is uniquely positioned to integrate stress information and also has neurons that project to the sites involved in blood pressure regulation such as the AV3V region. Stimulation of the BNST mimics stress-induced neuroendocrine and autonomic responses, i.e. elevation of blood pressure, increased catecholamines and corticotropin-releasing hormone (CRH) release. In the proposed studies, we will investigate the role of BNST and CRH in blood pressure regulation and peripheral vascular inflammation in a setting of stress-induced hypertension. Using Cre-lox technology, we plan to use genetically modified mice that will allow us to specifically identify CRH producing cells in the BNST as well as the ability to delete genes such as angiotensinogen in CRH producing neurons. We hypothesize that increased CRH release within the BNST is required for stress-induced hypertension and that this CRH- and BNST involvement in hypertension is dependent on increased T lymphocyte activation and peripheral vascular inflammation. These studies will provide new information for the central and peripheral mechanisms that mediate inflammatory diseases such as hypertension and may provide a better understanding for the link between the negative impact of stress on cardiovascular disease development. The combined expertise in the pathophysiology of hypertension, stress, translational neuroscience and neuroimmunology afford us a unique opportunity to pursue this research.
Psychological stress, hypertension and inflammation have been linked to cardiovascular disease progression, however the central and peripheral mechanisms are unclear. This project will test the hypothesis that stress induced changes in blood pressure and peripheral adaptive immunity are linked to specific neurohormonal stress circuits in the forebrain. These studies will provide new information regarding the central and peripheral mechanisms for the impact of stress and inflammation on hypertension and cardiovascular disease development.
|Marvar, Paul J; Hendy, Emma B; Cruise, Thomas D et al. (2016) Systemic leukotriene B4 receptor antagonism lowers arterial blood pressure and improves autonomic function in the spontaneously hypertensive rat. J Physiol 594:5975-5989|
|Pijacka, Wioletta; McBryde, Fiona D; Marvar, Paul J et al. (2016) Carotid sinus denervation ameliorates renovascular hypertension in adult Wistar rats. J Physiol 594:6255-6266|
|Andero, Raül; Daniel, Sarah; Guo, Ji-Dong et al. (2016) Amygdala-Dependent Molecular Mechanisms of the Tac2 Pathway in Fear Learning. Neuropsychopharmacology 41:2714-22|
|Keifer Jr, Orion P; Hurt, Robert C; Ressler, Kerry J et al. (2015) The Physiology of Fear: Reconceptualizing the Role of the Central Amygdala in Fear Learning. Physiology (Bethesda) 30:389-401|
|Brudey, Chevelle; Park, Jeanie; Wiaderkiewicz, Jan et al. (2015) Autonomic and inflammatory consequences of posttraumatic stress disorder and the link to cardiovascular disease. Am J Physiol Regul Integr Comp Physiol 309:R315-21|
|Hurt, R C; Garrett, J C; Keifer Jr, O P et al. (2015) Angiotensin type 1a receptors on corticotropin-releasing factor neurons contribute to the expression of conditioned fear. Genes Brain Behav 14:526-33|
|Marvar, Paul J; Goodman, Jared; Fuchs, Sebastien et al. (2014) Angiotensin type 1 receptor inhibition enhances the extinction of fear memory. Biol Psychiatry 75:864-72|