Peripheral arterial disease is a major cause of disability and limb loss and itself carries a substantial increase in cardiovascular and all-cause mortality, such that its prevalence and case fatality rate exceeds that for AIDS. The principle physiological response to PAD is collateral artery enlargement, a form of arteriogenesis. The long-term goals of our research program are to elucidate the cellular and molecular mechanisms responsible for collateral artery enlargement and the mechanisms by which cardiovascular risk factors impair this process. Recent work in our laboratory shows that hematopoietic stem cells (HSCs) are a primary determinant of collateral artery enlargement and hypercholesterolemia impairs many of the HSC-dependent mechanisms of post-ischemic neovascularization. The Project Hypothesis of this grant is: Hypercholesterolemia-induced oxidant stress, through epigenetic mechanisms, restricts the differentiation of HSCs towards vascular cells as well as towards pro-angiogenic monocytes and rather skews their differentiation towards pro-inflammatory monocytes thereby attenuating post-ischemic neovascularization. We will test our Project Hypothesis with the following Aims:
Specific Aim 1 : Determine the effect of hypercholesterolemia-induced oxidant stress on HSCs differentiation into vascular cells during post-ischemic neovascularization.
Specific Aim 2 : Determine the effects of hypercholesterolemia-induced oxidant stress on HSC differentiation towards pro-angiogenic monocyte intermediates, CD11blow and Ly6C low populations during post-ischemic neovascularization.
Specific Aim 3 : Identify the epigenetic mechanisms which regulate the HSC response to hypercholesterolemia- induced oxidant stress and impairs their differentiation towards pro-angiogenic monocytes during post-ischemic neovascularization. To accomplish these aims, we will establish in vitro differentiation assays that will serve as a framework to identify and correct the epigenetic changes responsible for hypercholesterolemia-induced HSC dysfunction. In vivo transplantation models will allow us to identify epigenetic-dependent clinical consequences of hypercholesterolemia-induced HSC oxidant stress. We will also utilize these in vivo models to reverse hypercholesterolemia- induced impairments in HSC function as preclinical studies intended to evaluate new therapeutic interventions. We will also assess the impact of hypercholesterolemia on human HSC function in vitro and utilize advanced humanized mouse models for in vivo studies, thereby increasing the scientific and clinical impact of our studies. Finally, we will utilize multiple techniques to identify the epigenetic marks induced in HSCs by hypercholesterolemia on a genome-wide scale. We believe that the results of these studies will introduce novel scientific findings that will be of substantial clinical impact.

Public Health Relevance

Peripheral arterial disease is a major cause of disability and limb loss and itself carries a substantial increase in cardiovascular and all-cause mortality such that its prevalence and case fatality rate exceeds that for AIDS. The principle physiological response to PAD is collateral artery enlargement, the key component of post-ischemic neovascularization. The long-term goals of our research program are to elucidate the cellular and molecular mechanisms responsible for collateral artery enlargement and the mechanisms by which cardiovascular risk factors impair this process

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01HL124101-01
Application #
8764380
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Ershow, Abby
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Surgery
Type
Schools of Medicine
DUNS #
City
Worcester
State
MA
Country
United States
Zip Code
01655