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Reversing Microvascular Dysfunction in Advancing Age

Award Number: R01AG053585
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2017
PERIOD OF PERFORMANCE END DATE: 02/28/2023

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Reversing Microvascular Dysfunction in Advancing Age - Coronary blood flow (BF) reserve (or the ability of the small coronary vessels to increase BF in response to increased workload) declines in senescent animals and humans and may contribute in the increased risk for cardiovascular disease (CVD) as a person ages. In addition to this baseline deterioration of coronary microvascular function, there are some distinct gender-related symptoms of CVD that have gone untreated. As many as 50% of women referred for evaluation of myocardial ischemia do not have obstructive coronary disease (like most men) but are frequently associated with coronary microvascular dysfunction/ischemia. Unfortunately, most traditional therapeutic treatments of CVD and myocardial ischemia were designed to address symptoms displayed by a majority of men (with obstructive large coronary vessels), but these methods are not applicable to treating women with microvascular ischemia. To address the clinical need for an effective microvessel-targeted therapy, we developed an adipose-derived stromal vascular fraction (SVF) cell therapy and demonstrated that the cells improved the microvascular coronary blood flow (CBF) and vasoactivity in aged rats. Furthermore, the therapeutic use of SVF cells improves tissue perfusion independent of vessel density. Building on this observation, additional findings have determined that the intravenous (i.v.) delivery of autologous, SVF cells reduced the resting tone of peripheral vasoactive arteries due to the injected SVF cells spontaneously populating the walls of these arteries in a hydrogen-peroxide-dependent manner. Therefore, we hypothesize that the i.v. delivery of freshly isolated adipose SVF cells will improve CBF in aged female rats by populating the walls of small coronary arteries/arterioles promoting vessel relaxation. To test this, we will use an aged female rat model combined with transgenic reporter-based cell tracking and functional assessment approaches to determine if coronary microvascular dysfunction can be reversed through SVF cell injection (Aim 1), to determine the effect of SVF cell incorporation on vascular network function (Aim 2), and which cell population from the SVF is contributing to the reversal of coronary microvascular dysfunction (Aim 3). To date, there a lack of cellular therapy designed to treat dysfunctional coronary microvessels as a result of advanced age, and this particular autologous cellular therapy has high clinical potential with findings applicable to a broad array of other microvascular disorders. In addition, we foresee our findings to have broad therapeutic relevance and provide new insight into the dynamics of vessel wall homeostasis and microvascular disease.


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 = -$2,171 )
2024	2021	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Aging Research	000	5	12/4/2023	NON-COMPETING CONTINUATION	-$2,171
														Subtotal = -$2,171

Issue Date FY: 2021 ( Subtotal = $313,759 )
2021	2021	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Aging Research	000	5	2/19/2021	NON-COMPETING CONTINUATION	$313,759
														Subtotal = $313,759

Issue Date FY: 2020 ( Subtotal = $313,816 )
2020	2020	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Aging Research	000	4	2/18/2020	NON-COMPETING CONTINUATION	$313,816
														Subtotal = $313,816

Issue Date FY: 2019 ( Subtotal = $297,045 )
2019	2019	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Aging Research	000	3	2/21/2019	NON-COMPETING CONTINUATION	$297,045
														Subtotal = $297,045

Issue Date FY: 2018 ( Subtotal = $444,586 )
2018	2018	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Aging Research	001	2	4/11/2018	NON-COMPETING CONTINUATION	$31,393
2018	2018	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Aging Research	002	2	9/8/2018	SUPPLEMENT FOR EXPANSION	$130,662
2018	2018	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Aging Research	000	2	1/19/2018	NON-COMPETING CONTINUATION	$282,531
														Subtotal = $444,586

Issue Date FY: 2017 ( Subtotal = $294,935 )
2017	2017	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Aging Research	000	1	2/27/2017	NEW	$294,935
														Subtotal = $294,935

Grand Total All Awards = $1,661,970

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Reversing Microvascular Dysfunction in Advancing Age

Award Number: R01AG053585

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2017

PERIOD OF PERFORMANCE END DATE: 02/28/2023

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