Coarctation of the aorta (COA) is the most common congenital vascular defect. It is characterized by local narrowing of the aorta and treatment is recommended by 5 years of age. Supravalvular aortic stenosis (SVAS) is a less common congenital defect that is also characterized by local aortic narrowing. About 60% of infants diagnosed with SVAS require surgical intervention to improve heart function. Complications of COA and SVAS treatment include operative mortality, aneurysms and recoarctation requiring reoperation. In both COA and SVAS, elastic fiber fragmentation suggests that elasticity and mechanical properties of the wall may be important for disease pathology. The mechanical properties of the wall and the hemodynamic forces, blood pressure and blood flow, change significantly in late embryonic development when the arterial narrowing occurs. The proposed research will test the hypothesize that arterial narrowing is caused by altered smooth muscle cell (SMC) phenotype in response to changes in the mechanical environment during late embryonic development. The proposed research will also determine if arterial narrowing can be prevented by changing the mechanical environment during targeted developmental periods through alterations in arterial elasticity or reduced blood pressure. The hypothesis will be tested using genetically-modified mice and pharmaceutical treatments. Three mouse models with reduced arterial elasticity caused by knockouts of different proteins, elastin (Eln), fibulin-4 (Fbln4) and lysyl oxidase (Lox) will be used. Elastin is the primary component of elastic fibers in the arterial wall;fibulin-4 is necessary for proper assembly of the elastic fibers;and lysyl oxidse crosslinks the soluble form of elastin into its mechanically functional form. All three mouse lines are perinatal lethal and show local aortic narrowing, but the mechanical environment has not been characterized. Two conditional mouse lines that turn elastin on or off during late embryonic development will also be used to determine if changing the arterial elasticity minimizes, prevents or delays narrowing. Lastly, established anti- hypertensive drugs will be used to reduce blood pressure during late embryonic development and determine if reducing the hemodynamic stress on the SMCs minimizes, prevents or delays arterial narrowing. In all cases, blood pressure, blood flow and arterial mechanical properties will be measured to quantify the mechanical environment. Ultrastructural studies and targeted gene array analysis will determine how the mechanical environment affects the extracellular matrix (ECM) and SMC phenotype. These studies will be important for identifying the mechanical and genetic pathways that lead to arterial narrowing in diseases such as COA and SVAS and will test preventative treatments.

Public Health Relevance

The most common congenital vascular defect is coarctation of the aorta, which has a mortality rate of 75% by 45 years of age if untreated. Treatment is usually recommended before 5 years of age and treatment complications include operative mortality, recoarctation and aneurysms. The goal of the proposed research is to test the hypothesis that coarctation is caused by changes in the vascular cell phenotype when there are alterations in the mechanical environment and that coarctation can be prevented by reversing the changes in the mechanical environment.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01HL115560-04
Application #
8656808
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Evans, Frank
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Washington University
Department
Engineering (All Types)
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Le, Victoria P; Yamashiro, Yoshito; Yanagisawa, Hiromi et al. (2014) Measuring, reversing, and modeling the mechanical changes due to the absence of Fibulin-4 in mouse arteries. Biomech Model Mechanobiol 13:1081-95
Gabriela Espinosa, M; Gardner, William S; Bennett, Lisa et al. (2014) The effects of elastic fiber protein insufficiency and treatment on the modulus of arterial smooth muscle cells. J Biomech Eng 136:021030