The large arteries function as elastic reservoirs for blood ejected by the heart. They distend during systole and relax during diastole, pushing blood to distal vessels and dampening the pressure pulse wave. This windkessel function also reduces left ventricular (LV) afterload and improves coronary blood flow and LV relaxation. In disease and aging, arterial compliance is reduced, which compromises the arterial windkessel function and increases the risk of death from heart disease. Recent evidence suggests that local decreases in compliance of the ascending aorta alone, rather than global decreases in arterial compliance, can cause adverse effects on cardiac function. The aortic compliance depends on the applied blood pressure, geometry, and material properties of the wall. The passive material properties are determined mostly by the amount and organization of extracellular matrix (ECM) proteins, including elastin and collagen. One way useful way to quantify the aortic material properties is to calculate the slope, or modulus, of the circumferential stretch-stress curve at physiologic pressure. Experimental evidence shows that this modulus is constant across different developmental ages, mouse models of human disease, and organisms, suggesting a universal elastic modulus that is a physiological design constraint. We hypothesize that the need to maintain a constant elastic modulus directs the construction of the ascending aorta to minimize LV afterload and the work done by the heart. We propose that smooth muscle cells (SMCs) orchestrate this process by directed growth and proliferation, and production of ECM proteins in the right amount, location, and organization to create an aortic wall with specific material properties and that this process is regulated through TGF- activity. We postulate that mathematical models incorporating hemodynamic forces, mechanical behavior, and physiological constants, can be used to better understand and predict this growth and remodeling process. We will test our hypothesis using novel mouse models in which elastin amounts and timing can be modulated. By understanding how SMCs create and maintain the aortic wall with a universal elastic modulus, and the extreme conditions in which the modulus cannot be maintained, we can gain information that will be useful in treating cardiovascular diseases related to decrease aortic compliance. These diseases include genetic defects that specifically alter the available ECM proteins for wall construction (i.e. supravalvular aortic stenosis, Marfan Syndrome, and vascular tortuosity syndromes), as well as those related to general decreases in compliance, such as coarctation of the aorta and systolic hypertension.
Our specific aims are to: 1) Determine how the need to maintain a universal elastic modulus directs aortic wall growth through regulation of TGF- activity; 2) Quantify how elastin and collagen amounts and organization interact to maintain a universal elastic modulus; 3) Integrate mechanical and physiological data into a mathematical model of aortic growth and remodeling.

Public Health Relevance

This project seeks to elucidate the mechanisms that lead to conduit artery stiffening in the context of hypertension and explore the temporal relationship between arterial stiffening and the development of hypertension in animal models.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL105314-05A1
Application #
8886630
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
OH, Youngsuk
Project Start
2010-09-20
Project End
2019-02-28
Budget Start
2015-04-15
Budget End
2016-02-29
Support Year
5
Fiscal Year
2015
Total Cost
$381,250
Indirect Cost
$131,250
Name
Washington University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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