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Microvascular Mechanisms Underlying Persistent Vessel Dysfunction Following Preeclampsia

Award Number: F32HL129677
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/08/2015
PERIOD OF PERFORMANCE END DATE: 03/02/2018

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Microvascular Mechanisms Underlying Persistent Vessel Dysfunction Following Preeclampsia - ¿ DESCRIPTION (provided by applicant): Cardiovascular disease remains a major public health problem and is the leading cause of death in the United States. Epidemiological data have illustrated that otherwise healthy women who develop preeclampsia during pregnancy are at a significantly (2-4 times) greater risk for the development of cardiovascular disease; however the mechanism(s) responsible for this association are unclear. One immerging hypothesis for this association is irreversible endothelial damage sustained during the preeclamptic pregnancy. Healthy women with a history of preeclamptic pregnancy demonstrate increased arterial stiffness and reduced endothelium- dependent vasodilation compared to women with a history of uncomplicated pregnancy, yet few, if any, human studies have sought to investigate the mechanism(s) responsible for this persistent vessel dysfunction. Rodent models of preeclampsia point to mechanistic roles for angiotensin II (ang II) and endothelin-1(ET-1) in the vessel dysfunction associated with preeclamptic pregnancy. These data suggest that changes in ang II and ET-1 signaling may lead to a pro-constrictor milieu in which attenuated endothelium-dependent vasodilation and reduced nitric oxide (NO) bioavailability result in exaggerated constriction and persistent vessel dysfunction following preeclamptic pregnancy. Therefore, the overarching goal of this proposal is to explore the mechanisms - both augmented constriction and attenuated endothelium-dependent dilation - by which ang II and ET-1 may contribute to this vessel dysfunction. We propose to utilize the human cutaneous circulation, a representative microvascular bed, to investigate microvascular signaling mechanisms in vivo in postpartum women who have had a preeclamptic pregnancy and postpartum control women who have had a normal pregnancy. In specific aim 1 we hypothesize that women who have had a preeclamptic pregnancy will have an attenuated endothelium-dependent vasodilation response to local skin heating (physiological stimulus) and exogenous acetylcholine (pharmacological stimulus) compared to women who have had a healthy pregnancy. In specific aim 2 we hypothesize that women who have had a preeclamptic pregnancy will have a greater vasoconstrictor response to exogenous ang II and ET-1 administration. Furthermore, we hypothesize that these alterations will be mediated by decreased NO bioavailability downstream of changes in ang II sensitivity and ET-1 receptor signaling. Intradermal microdialysis for the delivery of pharmacological agents directly to the cutaneous vascular bed, coupled with laser-Doppler flux for the measurement of cutaneous blood flow, will be used to pharmacodissect the proposed cellular mechanisms contributing to microvascular dysfunction in this population. This comprehensive assessment of the mechanisms that mediate the persistent microvascular dysfunction following preeclampsia directly translates the functional and molecular findings of cell and animal studies to a clinical population and will lend insight into the management of chronic elevated CVD risk in women who have suffered a preeclamptic pregnancy.


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: 2021 ( Subtotal = -$9,672 )
2021	2017	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Cardiovascular Diseases Research	000	3	12/28/2020	NON-COMPETING CONTINUATION	-$9,672
														Subtotal = -$9,672

Issue Date FY: 2018 ( Subtotal = -$30,602 )
2018	2017	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Cardiovascular Diseases Research	000	3	5/8/2018	NON-COMPETING CONTINUATION	-$30,602
														Subtotal = -$30,602

Issue Date FY: 2017 ( Subtotal = $59,897 )
2017	2017	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Cardiovascular Diseases Research	001	3	8/18/2017	NON-COMPETING CONTINUATION	$59,166
2017	2017	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Cardiovascular Diseases Research	000	2	12/26/2016	SUPPLEMENT FOR EXPANSION	$731
														Subtotal = $59,897

Issue Date FY: 2016 ( Subtotal = $56,118 )
2016	2016	PENNSYLVANIA STATE UNIVERSITY	110 TECHNOLOGY CENTER BUILDING	UNIVERSITY PARK	PA	16802	CENTRE	USA	Cardiovascular Diseases Research	000	2	8/10/2016	NON-COMPETING CONTINUATION	$56,118
														Subtotal = $56,118

Issue Date FY: 2015 ( Subtotal = $52,406 )
2015	2015	PENNSYLVANIA STATE UNIVERSITY	110 TECHNOLOGY CENTER BUILDING	UNIVERSITY PARK	PA	16802	CENTRE	USA	Cardiovascular Diseases Research	000	1	9/8/2015	NEW	$52,406
2015	2015	PENNSYLVANIA STATE UNIVERSITY	110 TECHNOLOGY CENTER BUILDING	UNIVERSITY PARK	PA	16802	CENTRE	USA	Cardiovascular Diseases Research	001	1	9/8/2015	NEW	$0
														Subtotal = $52,406

Grand Total All Awards = $128,147

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Microvascular Mechanisms Underlying Persistent Vessel Dysfunction Following Preeclampsia

Award Number: F32HL129677

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/08/2015

PERIOD OF PERFORMANCE END DATE: 03/02/2018

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