Mechanical Forces play important roles in the normal development and maintenance of blood vessel structure. Perturbations in the normal mechanical environment contribute to the pathological remodeling associated with diseases such as atherosclerosis, hypertension, and aneurysm formation. In the current proposal we will investigate the interrelationship between mechanical-induced remodeling and transforming growth factor-beta (TGF-?) bioavailability and activation from the latent complex in the extracellular matrix. To this end we will use a newly developed ex vivo mouse carotid culture system in which arteries can be cultured under precise mechanical environments for periods of hours to days to better understand the role of increased vascular wall stress, caused by pathological changes in the luminal pressure, modulates the growth and remodeling of the arteries. We will use this system to investigate the hypothesis that changes in wall stress in response to increased blood pressure modulates bioavailability of TGF-?, which contributes to growth and remodeling of arteries. To this end, we will test the role of specific components of the pathways that regulate TGF-? availability and signaling through the use of mice in which these components have been genetically manipulated. We will address the following specific aims to test our hypothesis: 1) To determine the role of av?5 integrin and smooth muscle 1-actin in mediating mechanosensitive activation of the TGF-? complex in the vascular wall. Carotid arteries from mice that are null for these genes will be used to test whether these proteins contribute to the mechanical activation of TGF-?. Understanding better interaction between ECM bound latent TGF-? and mechanical stresses in the vascular wall may aid in our understanding of local vascular remodeling events such as where aneurysms form and how the vascular wall responds to pressure changes. Additionally, these studies may aid in the development of scaffolding for tissue engineering.
The goals of this study are to determine if changes in the arterial wall in response to increased blood pressure result in activation of transforming growth factor-?. Transforming growth factor-? plays an important role in regulating changes in arteries during various pathologies so a better understanding of these interactions is important to understanding the early events in hypertension, aneurysm formation, and other vascular pathologies.
| Howell, David W; Popovic, Natasa; Metz, Richard P et al. (2014) Regional changes in elastic fiber organization and transforming growth factor ? signaling in aortas from a mouse model of marfan syndrome. Cell Tissue Res 358:807-19 |
