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Angiotensin-sensitive neurons in the nucleus of the solitary tract mediate social stress induced hypertension

Award Number: R01HL136595
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary Despite therapeutic advances, ~20% of patients with hypertension have uncontrolled high blood pressure, a condition that is associated with dysfunction in brain cardiovascular control centers. Therefore, there is a critical need to understand the neural pathways involved in cardiovascular regulation and how their dysfunction contributes to high blood pressure. This is particularly important for hypertension that is induced by chronic social stress, a major problem in today’s world, which involves activation of neuroendocrine and autonomic mechanisms. Our previous studies using novel genetic mouse models, viral-mediated gene transfer and optogenetics have revealed angiotensin type-2 receptor (AT2R)-containing neural pathways within the nucleus of the solitary tract (NTS) as important anti-hypertensive targets. Activation of AT2R-containing NTS neurons [referred to as NTSAT2R neurons] elicits profound increases in blood pressure; in contrast the AT2R(s) themselves serve a negative regulatory function, as their activation decreases blood pressure under both normal and hypertensive conditions. Based on our findings, we have developed the hypothesis that NTSAT2R neurons are a critical component of the neural pathways that mediate hypertension induced by chronic social stress. Specifically, we predict that during chronic social stress their activity is driven by excitatory (glutamatergic) inputs from the paraventricular nucleus of the hypothalamus (PVN), and that they in turn raise blood pressure via two mechanisms: Activation of GABAergic NTSAT2R neurons, which are the largest population of AT2R containing cells in the NTS, elicits baroreflex inhibition; Activation of Glutamatergic NTSAT2R neurons, which project to higher order brain regions such as the PVN, increases sympathetic outflow and neuroendocrine secretion. We further predict that selective activation of AT2R(s) present on NTS neurons will offset social stress-induced hypertension by restoring baroreflex function and normalizing sympathetic outflow and neuroendocrine secretions. Our overall hypothesis will be tested in three Aims that utilize a novel model of hypertension in mice (Chronic Social Defeat Stress [CSDS]) along with genetic (e.g., optogenetic and chemogenetic) and pharmacological approaches. Aim 1: Dissecting a specific neural circuit that impinges on and regulates NTSAT2R neurons, will test the specific hypothesis that PVN inputs to NTSAT2R neurons are necessary and sufficient to promote CSDS hypertension. Aim 2: Investigating distinct mechanistic roles for GABAergic vs. glutamatergic NTSAT2R neurons in regulation of blood pressure during hypertension, will test the specific hypothesis that GABAergic NTSAT2R neurons inhibit the baroreflex, while glutamatergic PVN-projecting NTSAT2R neurons stimulate vasopressin neurons and sympathetic outflow. Aim 3: Targeting NTSAT2R neurons to alleviate CSDS hypertension, will test the specific hypotheses that NTSAT2R neurons are necessary for the development of CSDS hypertension, and that these neurons or AT2R may be targeted to alleviate it. Collectively, these studies will provide mechanistic insight that may direct development of novel therapeutics to treat hypertension induced by social stress.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $569,687 )
2024	2024	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION INC	58 EDGEWOOD AVE NE	ATLANTA	GA	30303	FULTON	USA	Cardiovascular Diseases Research	005	6	4/8/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$502,670
2024	2024	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION INC	58 EDGEWOOD AVE NE	ATLANTA	GA	30303	FULTON	USA	Cardiovascular Diseases Research	001	6	12/11/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$569,687
2024	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	004	5	4/8/2024	COMPETING CONTINUATION	-$502,670
2024	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	003	5	2/27/2024	COMPETING CONTINUATION	$0
2024	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	000	5	12/7/2023	COMPETING CONTINUATION	$0
2024	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	002	4	2/27/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $569,687

Issue Date FY: 2023 ( Subtotal = $618,784 )
2023	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	000	5	3/13/2023	COMPETING CONTINUATION	$618,784
														Subtotal = $618,784

Issue Date FY: 2021 ( Subtotal = $564,976 )
2021	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	001	4	8/11/2021	NON-COMPETING CONTINUATION	$56,499
2021	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	000	4	11/17/2020	NON-COMPETING CONTINUATION	$508,477
														Subtotal = $564,976

Issue Date FY: 2020 ( Subtotal = $564,976 )
2020	2020	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	000	3	1/7/2020	NON-COMPETING CONTINUATION	$536,726
2020	2020	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	001	3	1/25/2020	NON-COMPETING CONTINUATION	$28,250
														Subtotal = $564,976

Issue Date FY: 2019 ( Subtotal = $564,976 )
2019	2019	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	000	2	12/18/2018	NON-COMPETING CONTINUATION	$564,976
														Subtotal = $564,976

Issue Date FY: 2018 ( Subtotal = $580,226 )
2018	2018	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	000	1	12/6/2017	NEW	$580,226
														Subtotal = $580,226

Grand Total All Awards = $3,463,625

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Angiotensin-sensitive neurons in the nucleus of the solitary tract mediate social stress induced hypertension

Award Number: R01HL136595

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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