Stressful life events contribute to the etiology of anxiety and hypertension and increase the risk for cardiovascular disease, which is the leading cause of death in the U.S. Despite a myriad of research, nearly one-third of patients with anxiety and/or hypertension are resistant to current treatments and understanding the pathophysiology underlying these disorders is necessary to identify novel therapeutics. Stressors perceived in the environment or those arising from the internal milieu create neural signals that converge on the paraventricular nucleus of the hypothalamus (PVN), which integrates these signals and transduces them into cardiovascular, neuroendocrine and behavioral responses. Chronic unpredictable stress elicits gene x environment interactions that promote neurochemical plasticity within the PVN that heighten stress responsiveness and promote affective and cardiovascular disorders. A premise of this proposal is that angiotensin receptor signaling within the PVN is a key mediator of gene x environment interactions that control cardiovascular reactivity, neuroendocrine axes and anxiety subsequent to chronic stress. Traditionally, the RAS is considered an endocrine system that elevates blood pressure by increasing the binding of angiotensin II (Ang-II) to its angiotensin type-1 receptor (AT1R). However, we recently found that optogenetic activation of neurons in the PVN that express AT1R(s) augment, but optogenetic inhibition or selective deletion of AT1R(s) from the PVN dampen stress responding in mice. Concomitantly, we evaluated the influence of brain angiotensin converting enzyme 2 (ACE2) on stress responding. Angiotensin converting enzyme 2 metabolizes Ang-II into angiotensin 1-7 which promotes cardio- protection, in part, by activating Mas receptors. Interestingly, we discovered that up-regulating ACE2 activity in the brain potently dampens stress responding in mice. Collectively, these observations have led to our overall hypothesis that balance between AT1R stimulation and ACE2 activity dictates excitation or inhibition of specific neuronal phenotypes within the PVN to promote susceptibility or resiliency to stress-related disease. We propose the following specific aims to substantiate or refute this hypothesis.
Aim 1 uses mice with Cre recombinase directed to AT1R(s) and in vivo optogenetics to test the hypothesis that chronic excitation of AT1R-expressing neurons in the PVN recapitulates the pathophysiology that follows chronic stress.
Aim 2 uses mice with AT1R selectively deleted from the PVN to test the hypothesis that such receptors mediate gene x environment interactions that exaggerate stress responding subsequent to chronic stress.
Aim 3 uses mice with ACE2 overexpression directed to neurons that synthesize corticotrophin-releasing-hormone (CRH) to test the hypothesis that CRH-ACE2 interactions relieve chronic stress-induced pathophysiology. Collectively, the proposed research will reveal, at a very detailed and mechanistic level, how brain angiotensin signaling contributes to the etiology of stress-related disease and will inform on novel therapeutics.

Public Health Relevance

Stressful life events contribute to the onset of anxiety-disorders and hypertension, which increase the risk for cardiovascular disease, is the leading cause of death in the U.S. This project attempts to target angiotensin receptor signaling within the brain to understand and alleviate these stress-related diseases. Completion of the proposed studies may result in novel therapeutics for comorbid affective and cardiovascular disorders.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL139868-01
Application #
9423471
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
Maric-Bilkan, Christine
Project Start
2017-12-01
Project End
2021-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Florida
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611