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.

Public Health Relevance

To date, there are no known treatments to improve coronary microvascular dysfunction that occurs in advancing age. The purpose of this study is to evaluate the safety and efficacy of a regenerative cell- based therapy to repair or restore coronary microvascular function, potentially through the incorporation of injected regenerative cells into the vascular wall. This study will improve our understanding of age-related cell therapy and the mechanism for which cell type in adipose tissue mediates vascular dysfunction reform upon incorporation.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG053585-01A1
Application #
9309164
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Kohanski, Ronald A
Project Start
2017-03-01
Project End
2022-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
1
Fiscal Year
2017
Total Cost
$294,935
Indirect Cost
$89,935
Name
University of Louisville
Department
Physiology
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40208
LeBlanc, Amanda J; Kelm, Natia Q (2017) Thrombospondin-1, Free Radicals, and the Coronary Microcirculation: The Aging Conundrum. Antioxid Redox Signal 27:785-801