It is established that the central nervous system (CNS) contributes to the long-term regulation of blood pressure in both health and disease via effects on neuroendocrine mechanisms and sympathetic outflow. Specifically, elevations in baseline and stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis activity and sympathetic nervous system function are implicated in the etiology of hypertension in humans and in related animal models including the spontaneously hypertensive rat (SHR). However, CNS mechanisms that mediate chronic increases in baseline blood pressure and/or stress reactivity are inadequately understood. The overall goal of our research program is to elucidate mechanisms within the brain that mediate chronic changes in baseline and stress-activated blood pressure regulation. The experiments in this application focus on regulatory mechanisms within the paraventricular nucleus (PVN) of the hypothalamus. Neurons within the PVN are critical to the central regulation of both the HPA axis and the sympathetic nervous system, and angiotensin II (Ang II) acting within the PVN has emerged as one key neuropeptide that can activate both of these outputs. We have recently identified macrophage migration inhibitory factor (MIF) as an intracellular negative regulator of the excitatory actions of Ang II in normotensive rat neurons. Collectively, our studies indicate that MIF acts within PVN neurons of normotensive rats via its intrinsic thiol protein oxidoreductase (TPOR) activity to attenuate the cardiovascular actions of Ang II. However, our data indicate this regulatory mechanism is absent from PVN neurons of SHR, and that long-term replacement of MIF within SHR neurons blunts the age-related increase in baseline blood pressure observed in this model of hypertension. These results establish an important role for MIF in attenuating the excitatory effects of Ang II, acting within the PVN, to promote age-related increases in baseline blood pressure. The present application specifically investigates the role of PVN MIF in the modulation of Ang II-mediated blood pressure regulation during acute and chronic stress, and potential contributions of both the HPA axis and the sympathetic nervous system to blood pressure regulation will be determined. The overall hypothesis is that replacement of MIF within PVN neurons of SHR will attenuate the increased blood pressure reactivity to stress observed in these animals by a mechanism that requires the TPOR activity of MIF. The specific goal is to test this hypothesis by utilizing AAV2-mediated gene delivery to chronically express MIF, or a mutant MIF protein that lacks TPOR activity, selectively in PVN neurons of SHR and normotensive control rats. This goal will be achieved via the following Specific Aims:
Aim 1 is to determine the effects of long-term viral-mediated expression of MIF within PVN neurons of SHR and normotensive rats on blood pressure regulation during acute and chronic stress.
Aim 2 is to determine the role of the TPOR moiety of MIF in mediating the effects of MIF within PVN neurons of SHR and normotensive rats on blood pressure regulation during acute and chronic stress.

Public Health Relevance

Current treatment of high blood pressure primarily targets symptoms rather than causes or prevention because the causes of high blood pressure are not established. It is now understood that people who have a high level of stress in their lives and/or react excessively to stress have an increased risk for high blood pressure. The goal of the proposed studies is to show that macrophage migration inhibitory factor in the brain is a key regulator of blood pressure at rest and during stress, thus providing a novel target for the prevention and treatment of high blood pressure.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Hypertension and Microcirculation Study Section (HM)
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Maric-Bilkan, Christine
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University of Florida
Schools of Medicine
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de Kloet, Annette D; Pitra, Soledad; Wang, Lei et al. (2016) Angiotensin Type-2 Receptors Influence the Activity of Vasopressin Neurons in the Paraventricular Nucleus of the Hypothalamus in Male Mice. Endocrinology 157:3167-80
de Kloet, Annette D; Wang, Lei; Ludin, Jacob A et al. (2016) Reporter mouse strain provides a novel look at angiotensin type-2 receptor distribution in the central nervous system. Brain Struct Funct 221:891-912
de Kloet, Annette D; Liu, Meng; Rodríguez, Vermalí et al. (2015) Role of neurons and glia in the CNS actions of the renin-angiotensin system in cardiovascular control. Am J Physiol Regul Integr Comp Physiol 309:R444-58
Erdos, Benedek; Clifton, Rebekah R; Liu, Meng et al. (2015) Novel mechanism within the paraventricular nucleus reduces both blood pressure and hypothalamic pituitary-adrenal axis responses to acute stress. Am J Physiol Heart Circ Physiol 309:H634-45
Erdos, Benedek; Backes, Iara; McCowan, Michael L et al. (2015) Brain-derived neurotrophic factor modulates angiotensin signaling in the hypothalamus to increase blood pressure in rats. Am J Physiol Heart Circ Physiol 308:H612-22
Sumners, Colin; de Kloet, Annette D; Krause, Eric G et al. (2015) Angiotensin type 2 receptors: blood pressure regulation and end organ damage. Curr Opin Pharmacol 21:115-21
Shi, Peng; Grobe, Justin L; Desland, Fiona A et al. (2014) Direct pro-inflammatory effects of prorenin on microglia. PLoS One 9:e92937
Freiria-Oliveira, André Henrique; Blanch, Graziela Torres; Li, Hongwei et al. (2013) Macrophage migration inhibitory factor in the nucleus of solitary tract decreases blood pressure in SHRs. Cardiovasc Res 97:153-60
de Kloet, Annette D; Krause, Eric G; Shi, Peng D et al. (2013) Neuroimmune communication in hypertension and obesity: a new therapeutic angle? Pharmacol Ther 138:428-40