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Angiotensin-(1-7) engages hypothalamic arcuate-paraventricular nucleus inhibitory pathways to lower blood pressure

Award Number: F31HL170693
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 08/01/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Angiotensin-(1-7) engages hypothalamic arcuate-paraventricular nucleus inhibitory pathways to lower blood pressure - PROJECT SUMMARY Obesity is a global epidemic that greatly increases the risk for developing hypertension and cardiovascular disease. The molecular mechanisms connecting hypertension with obesity are poorly understood, however, and optimal treatment strategies are unclear as some antihypertensive drugs elicit adverse metabolic side effects. This illustrates the critical need to identify new therapeutic targets with a positive metabolic profile for treatment of obesity hypertension. We propose that angiotensin (Ang)-(1-7), a protective hormone of the renin- angiotensin system, provides this ideal target. Ang-(1-7) binds mas receptors (masR) to lower blood pressure and improve metabolic function in obese and hypertensive rodents; but the mechanisms involved are unknown. Our preliminary data show that Ang-(1-7) depressor effects require activation of masR within the arcuate nucleus of the hypothalamus (ARC). More specifically, we show that Ang-(1-7) masR are highly localized to proopiomelanocortin (POMC)-containing neurons that release the inhibitory neurotransmitter GABA. Activation of GABAergic POMC neurons by Ang-(1-7) could lower blood pressure by inhibiting downstream melanocortin-4 receptor (MC4R) signaling in the hypothalamic paraventricular nucleus (PVN), but this has not been explored. This proposal will test the central hypothesis that Ang-(1-7) stimulates ARC POMC neurons to enhance GABAergic neurotransmission onto PVN neurons to lower blood pressure. Aim 1 will determine if POMC masR are required for Ang-(1-7) to inhibit PVN neuronal activity and lower blood pressure. To test this, we will employ a novel transgenic mouse model to determine if deletion of masR from POMC neurons prevents the ability of Ang-(1-7) to enhance GABAergic activity in the PVN and lower blood pressure under normal conditions and in the context of high fat diet-induced obesity hypertension. Aim 2 will determine if high fat diet decreases, and Ang-(1-7) treatment restores, GABAergic transmission onto MC4R-expressing PVN neurons. To test this, we will employ MC4R-GFP mice to determine if: high fat diet decreases inhibitory neurotransmission in MC4R-expressing PVN neurons, Ang-(1-7) treatment reverses these effects, and changes in inhibitory neurotransmission in MC4R-PVN neurons correlate with blood pressure. The findings from this proposal will provide new insight into the neural mechanisms by which Ang-(1-7) lowers blood pressure as well as the potential for therapeutic targeting of Ang-(1-7) in obesity hypertension. Importantly, this proposal will logically build upon the PI’s background in molecular neuroscience and allow her to develop a new skillset in integrated molecular and whole animal physiological and pharmacological methods to assess neural mechanisms engaged by Ang-(1-7) for cardiovascular regulation. The PI will receive strong mentorship and a research framework to establish an independent and novel area of research to help meet her long-term career goal of becoming an independent investigator at an academic research institution where she can conduct collaborative and clinically relevant cardiovascular neuroscience research.


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 = $35,788 )
2024	2024	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Cardiovascular Diseases Research	000	2	7/2/2024	NON-COMPETING CONTINUATION	$35,788
														Subtotal = $35,788

Issue Date FY: 2023 ( Subtotal = $34,508 )
2023	2023	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Cardiovascular Diseases Research	001	1	6/30/2023	NEW	$0
2023	2023	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Cardiovascular Diseases Research	000	1	6/30/2023	NEW	$34,508
														Subtotal = $34,508

Grand Total All Awards = $70,296

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Angiotensin-(1-7) engages hypothalamic arcuate-paraventricular nucleus inhibitory pathways to lower blood pressure

Award Number: F31HL170693

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 08/01/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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