Vascular homeostasis plays an important role in maintenance of normal vessel and organ function. Recent studies from our and other laboratories have established that continuous endothelial fibroblast growth factor (FGF) signaling input is critical for the maintenance of vascular integrity, permeability and cell fate. One particularly important consequence of the loss of FGF input is the development of endothelial-to-mesenchymal transition (EndMT) that represents a fate transition from endothelial to a mesenchymal-like (smooth muscle cell (SMC), fibroblast) phenotype. Induced by chronic inflammation and other poorly understood stimuli, EndMT leads to formation of neointima that consists of a combination of different cell types, SMCs, fibroblasts and various inflammatory cells as well as remodeling of the extracellular matrix (ECM). We have observed extensive EndMT in atherosclerotic coronary arteries in patients and in mouse atherosclerosis. These data suggest that EndMT may make a major contribution to disease progression in illnesses associated with chronic inflammation, such as atherosclerosis, and transplant arteriopathy. If correct, this hypothesis would open a possibility to fundamentally change the natural history of these illnesses with considerable clinical impact. To this end, we aim to test whether suppression of EndMT will inhibit will inhibit initiation, progression and regression of atherosclerotic lesions, and to unravel the signaling and gene expression pathways that connect EndMT, ECM remodeling and inflammation that mediate these effects.

Public Health Relevance

We have identified that a novel process, endothelial-to-mesenchymal transition, as potentially the key driving force behind atherosclerosis progression. The proof of this hypothesis will open new therapeutic possibilities for treating diseases such as heart attacks, stroke and peripheral vascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL135582-02
Application #
9412183
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Olive, Michelle
Project Start
2017-01-12
Project End
2020-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520