Thoracic aortic aneurysms (TAAs) develop as a consequence to abnormal remodeling of the aortic extracellular matrix (ECM). TAA development is influenced by a series of interrelated mechanisms that disrupt ECM homeostasis through the stimulation of proteolytic pathways, such as the matrix metalloproteinases (MMPs) and dysregulation of the production and deposition of ECM proteins. Importantly, these mechanisms are mediated in part through changes in the resident cellular constituents within the aortic wall. Numerous studies have demonstrated that aortic dilatation is accompanied by the apoptotic loss of smooth muscle cells, suggesting that the aortic fibroblast may be the key cellular mediator of ECM remodeling during aneurysm formation. Moreover, recent evidence from this laboratory suggests that aortic fibroblasts undergo a stable transformation to a myofibroblast phenotype, that is characterized by increased myosin staining (DDR2/Myh11) and enhanced production of both MMPs and ECM proteins. It is hypothesized that the transdifferentiation of fibroblasts is essential for TAA progression. However, the mediator(s) regulating this fibroblast-to-myofibroblast transition during TAA development remain undefined. One upstream signaling protein capable of regulating the structure and composition of the aortic ECM, and known to play an important role in mediating the fibroblast-to- myofibroblast transformation, is transforming growth factor-beta (TGF-?). TGF-? is a soluble peptide growth factor, produced by multiple cell types within the aortic wall, and is known to play a significant role in aortic root dilatation secondary to Marfan syndrome, but its involvement remains undefined in non-MFS etiologies of TAA. TGF-? is sequestered within the ECM, bound by latent TGF-? binding proteins. These latent complexes are proteolytic targets for key MMPs (MT1-MMP) that are induced during TAA development. Accordingly, using an established mouse model of TAA, and isolated primary aortic fibroblast cultures (normal and TAA), the role of fibroblast transdifferentiation in TAA development will be examined with the central hypothesis that MT1-MMP- dependent TGF-? signaling is essential for TAA development through the modulation of aortic fibroblast phenotype change. This hypothesis will be tested by demonstrating that selective targeting of fibroblast transdifferentiation can modulate TAA formation and progression, that increased TGF-? signaling during TAA development is a direct result of altered MT1-MMP-dependent release of TGF-? from latent ECM bound stores, and that indirect pharmacological inhibition of TGF-? signaling results in the attenuation of TAA development. The outcomes from this unified set of aims will establish a cause-effect relationship between MT1-MMP activation, TGF-? dependent myofibroblast differentiation, and TAA development.

Public Health Relevance

Thoracic aortic aneurysm (TAA) disease is an insidious process which often causes death by rupture in the absence of clinical symptoms. This project will establish a cause-effect relationship between fibroblast-to- myofibroblast transdifferentiation and TAA development. Moreover, it will establish MT1-MMP-dependent release of TGF-? as a primary determinant of myofibroblast differentiation during TAA formation, and will identify angiotensin II type-I recepto antagonism as a therapeutic modality for non-genetically derived TAA- subtypes.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
2I01BX000904-04A2
Application #
8818576
Study Section
Cardiovascular Studies B (CARB)
Project Start
2011-01-01
Project End
2018-09-30
Budget Start
2014-10-01
Budget End
2015-09-30
Support Year
4
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Ralph H Johnson VA Medical Center
Department
Type
DUNS #
039807318
City
Charleston
State
SC
Country
United States
Zip Code
29401
Tian, Yulong; Zhang, Wei; Sun, Jun et al. (2018) A reproducible swine model of proximal descending thoracic aortic aneurysm created with intra-adventitial application of elastase. J Vasc Surg 67:300-308.e2
Ikonomidis, John S; Nadeau, Elizabeth K; Akerman, Adam W et al. (2017) Regulation of membrane type-1 matrix metalloproteinase activity and intracellular localization in clinical thoracic aortic aneurysms. J Thorac Cardiovasc Surg 153:537-546
Jones, Jeffrey A (2017) Oxidative stress in bicuspid aortic valve-related aortopathy: Hand-me-downs and yoga pants. J Thorac Cardiovasc Surg 154:1764-1765
Ruddy, Jean Marie; Akerman, Adam W; Kimbrough, Denise et al. (2017) Differential hypertensive protease expression in the thoracic versus abdominal aorta. J Vasc Surg 66:1543-1552
Jones, Jeffrey A (2016) Editorial Commentary: Understanding Marfan syndrome, or ""how not to invent the light bulb"". Trends Cardiovasc Med 26:429-32
Ruddy, Jean Marie; Ikonomidis, John S; Jones, Jeffrey A (2016) Multidimensional Contribution of Matrix Metalloproteinases to Atherosclerotic Plaque Vulnerability: Multiple Mechanisms of Inhibition to Promote Stability. J Vasc Res 53:1-16
Jones, Jeffrey A (2015) Invited commentary. Ann Thorac Surg 99:71
Daskalova, Elena; Delchev, Slavi; Peeva, Yulia et al. (2015) Antiatherogenic and Cardioprotective Effects of Black Chokeberry (Aronia melanocarpa) Juice in Aging Rats. Evid Based Complement Alternat Med 2015:717439
Renaud, Ludivine; Harris, Lillianne G; Mani, Santhosh K et al. (2015) HDACs Regulate miR-133a Expression in Pressure Overload-Induced Cardiac Fibrosis. Circ Heart Fail 8:1094-104
McDonald, Lindsay T; Russell, Dayvia L; Kelly, Ryan R et al. (2015) Hematopoietic stem cell-derived cancer-associated fibroblasts are novel contributors to the pro-tumorigenic microenvironment. Neoplasia 17:434-48

Showing the most recent 10 out of 17 publications