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Contribution of estrogen receptor beta to changes in hypothalamic plasticity and hypertension susceptibility in mice with accelerated ovarian failure

Award Number: R01HL136520
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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ABSTRACT Hypertension is more prevalent in men than in young women, but as women progress towards menopause this relationship is reversed. Unfortunately, compared to men, menopausal women are less likely to receive optimal diagnostic evaluation and therapeutic intervention. In women, the increased incidence of hypertension begins at “perimenopause”, a transitional phase preceding and extending through menopause beginning at ~45-54 years of age. The perimenopausal period is accompanied by irregular estrous cycles and erratically fluctuating estrogen levels; it may also be a critical period for the emergence of brain plasticity that may contribute to the development of hypertension. The reversal of hypertension liability in young and older women may be phylogenetically conserved: aged female mice, but not young female mice, show increased sympathetic tone and blood pressure following slow-pressor angiotensin II (AngII) administration. To better understand the role of ovarian hormones in female hypertension, we have utilized a mouse model of accelerated ovarian failure (AOF) that uniquely recapitulates hormone fluctuations seen in human menopause. Using AOF mice, we made the novel finding that the susceptibility to hypertension begins at “peri-AOF”, which is a stage marked by irregular and extended estrous cycles similar to human perimenopause. In addition, peri-AOF hypertension was associated with a unique profile of N-methyl-D-aspartic acid (NMDA) receptor plasticity in estrogen receptor ß (ERß) containing neurons in the hypothalamic paraventricular nucleus (PVN) not seen in pre- or post-AOF females, or in males. These findings define peri-AOF as a critical period when hypertension and adaptations in neuro-cardiovascular regulatory systems emerge. In the current proposal, we will investigate the role of ERß in the emergence of hypertension and PVN NMDA receptor plasticity during peri-AOF. For this, we will test the central hypothesis that ERß influences the susceptibility to hypertension and NMDA receptor plasticity in select populations of PVN neurons in peri-AOF mice following slow-pressor AngII administration. Two aims will test this hypothesis. Aim 1 will test the sub- hypothesis that ERß in the PVN is critically involved in the susceptibility of peri-AOF females to hypertension and potentiated NMDA receptor-mediated excitatory signaling in CRF-expressing neurons. Aim 2 will test the sub-hypothesis that cyclic administration of ERß agonists during peri-AOF reduces both hypertension susceptibility and NMDA-mediated excitatory signaling selectively in CRF-containing PVN neurons. These studies will be achieved using a multidisciplinary approach including spatio-temporal deletion of the ERß gene, electron microscopic immunocytochemistry, molecular and biochemical assays and neurophysiological methods.


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 = $655,692 )
2024	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Cardiovascular Diseases Research	000	6	1/8/2024	NON-COMPETING CONTINUATION	$655,692
														Subtotal = $655,692

Issue Date FY: 2023 ( Subtotal = $759,387 )
2023	2023	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cardiovascular Diseases Research	001	5	12/14/2022	COMPETING CONTINUATION	$759,387
2023	2020	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cardiovascular Diseases Research	000	4	12/7/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $759,387

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cardiovascular Diseases Research	000	4	12/3/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $423,750 )
2020	2020	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	407 E 61ST ST RM 106 1ST FL	NEW YORK	NY	10065	NEW YORK	USA	Cardiovascular Diseases Research	000	4	2/10/2020	NON-COMPETING CONTINUATION	$423,750
														Subtotal = $423,750

Issue Date FY: 2019 ( Subtotal = $423,750 )
2019	2019	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	407 E 61ST ST RM 106 1ST FL	NEW YORK	NY	10065	NEW YORK	USA	Cardiovascular Diseases Research	000	3	1/31/2019	NON-COMPETING CONTINUATION	$423,750
														Subtotal = $423,750

Issue Date FY: 2018 ( Subtotal = $847,500 )
2018	2018	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	407 E 61ST ST RM 106 1ST FL	NEW YORK	NY	10065	NEW YORK	USA	Cardiovascular Diseases Research	001	2	6/23/2018	NON-COMPETING CONTINUATION	$8,475
2018	2018	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	407 E 61ST ST RM 106 1ST FL	NEW YORK	NY	10065	NEW YORK	USA	Cardiovascular Diseases Research	000	2	1/30/2018	NON-COMPETING CONTINUATION	$415,275
2018	2018	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	407 E 61ST ST RM 106 1ST FL	NEW YORK	NY	10065	NEW YORK	USA	Cardiovascular Diseases Research	002	2	9/14/2018	SUPPLEMENT FOR EXPANSION	$423,750
														Subtotal = $847,500

Issue Date FY: 2017 ( Subtotal = $423,750 )
2017	2017	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	407 E 61ST ST RM 106 1ST FL	NEW YORK	NY	10065	NEW YORK	USA	Cardiovascular Diseases Research	000	1	2/1/2017	NEW	$423,750
														Subtotal = $423,750

Grand Total All Awards = $3,533,829

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Contribution of estrogen receptor beta to changes in hypothalamic plasticity and hypertension susceptibility in mice with accelerated ovarian failure

Award Number: R01HL136520

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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