Endothelial cells play an important role in the maintenance of tissue homeostasis. Endothelial dysfunction, characterized by phenotypic and hemodynamic changes in blood vessels, is an early predictor of cardiovascular disease, the leading cause of death worldwide. Chronic oxidant injury to the endothelium during aging leads to endothelial senescence and development of a pro-inflammatory phenotype, increasing the risk of cardiovascular events such as myocardial infarction and stroke. Therefore, better understanding of the molecular mechanisms that regulate vascular aging and inflammation, is essential for the control of cardiovascular disease. The endothelium plays a critical role in inflammation by controlling the expression of cytokines and adhesion molecules involved in attraction, adhesion and infiltration of inflammatory cells. Consistent with the systemic distribution of the vascular network, endothelial cells are a potential source of inflammatory mediators in aging and chronic-inflammatory diseases. Although the identity of pro-inflammatory molecules is well known, the mechanisms that control their expression are complex and multifactorial. Therefore, more studies are needed to identify cellular mediators as well as central molecules and pathways that regulate senescence pro-inflammatory response under normal aging and pathological conditions. Our long-term goal is to develop interventions to preserve endothelial homeostasis, thus preventing vascular inflammation and associated cardiovascular disease. Our goal with the proposed study is to understand how endothelial cMyc regulates vascular aging and inflammation. Recent work from our group have identified a novel role for the transcription factor cMyc as a potential regulator of vascular senescence and inflammation. Our preliminary studies indicate that cMyc expression declines in human endothelial cells undergoing replicative senescence, and that this phenomenon is associated with increased expression of inflammation markers. We performed gene expression profiling studies in mice overexpressing cMyc specifically in endothelial cell lineage and observed a reduction in the expression of the senescence marker p21 and pro-inflammatory mediators with aging in different organs. These findings support the central hypothesis that cMyc is an essential regulator of senescence-associated vascular inflammation.
In Aim 1, we will determine how cMyc regulates vascular aging using wild-type and genetically engineered adult mice with conditional deletion of c-Myc specifically in endothelial lineage.
In Aim 2, we will investigate the contribution of cMyc to vascular inflammation using the mouse model described in Aim 1.
In Aim 3, we will identify cMyc downstream target genes that play a role in vascular aging and inflammation. For the 3 aims proposed, results will be compared to commercially available endothelial cells from young and aged donors. Completion of these aims will define novel mechanisms and potential therapeutic targets that control vascular aging and inflammation.

Public Health Relevance

Cardiovascular disease is the leading cause of death worldwide. It has been estimated that 1 in every 3 American adults have 1 or more types of cardiovascular disease and that 1 in every 6 will die of coronary heart disease. Endothelial dysfunction, which develops with aging and a large number of pathological conditions, is an early predictor of cardiovascular disease and increase the chances of vascular complications, such as atherosclerosis, myocardial infarction and stroke.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL128536-04
Application #
9985631
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Gao, Yunling
Project Start
2017-08-10
Project End
2021-07-31
Budget Start
2020-08-01
Budget End
2021-07-31
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146