The aims of this renewal application will continue to investigate how changes in elastin deposition and assembly influence blood vessel development and cardiovascular function. We also seek to understand how elastin mutations that alter elastic fiber assembly lead to vascular disease. During the previous funding period we showed a strong correlation between the rise in blood pressure and the increase in elastin production during development. Blood pressure and elastin synthesis increase coordinately through the fetal and postnatal period and blood pressure stabilizes when elastin production ends between P21-P30. Although there is no generally accepted explanation for what directs the changes in hemodynamics and SMC matrix production, wall stress is considered to be the major player. The ECM, in contrast, is regarded as a static component that contributes to the mechanical properties of the wall but otherwise has no say in the matter. We propose that H2O2 generated during elastic fiber formation acts as a signaling molecule to directly influence cellular differentiation and cardiac function as the cardiovascular system matures. Instead of the traditional view that alterations in blood pressure direct matrix production exclusively through signals associated with wall stress, our model suggests that reactive oxygen species (ROS) signals generated during active matrix synthesis and maturation influence adjustments in blood pressure and cell differentiation through direct signaling or by modulating mechanical signaling pathways. Because increases in blood pressure can only occur to the extent that they can be accommodated by the vessel wall, feedback signals from the structural components responsible for vessel integrity are an efficient way to signal the cardiovascular system that the wall has achieved the required strength and appropriate mechanical properties to accommodate changes in flow and pressure. Coupling signaling to crosslinking of elastin provides information about both elastin synthesis and, most importantly, the maturation state of elastin. Thus, the underlying hypothesis of this application is that ROS generated during elastin crosslinking provide a regulatory signal that influences smooth muscle cell differentiation and cardiovascular physiology. We also propose that elastin-derived ROS influence the angiotensin signaling pathway and that this pathway is responsible for the adaptive remodeling that occurs in elastin insufficiency.
Our specific aims are: 1) To explore a novel signaling mechanism mediated by reactive oxygen species generated during elastin crosslinking. 2) To determine how the renin-angiotensin system directs vascular remodeling in late gestation elastin insufficiency. 3) To explore treatment strategies designed to rescue elastin insufficiency (SVAS).

Public Health Relevance

This project seeks to understand the basic molecular mechanisms behind diseases associated with mutations in the elastin gene that affect vascular development and cardiovascular function.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL074138-06
Application #
7914163
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Gao, Yunling
Project Start
2003-07-01
Project End
2013-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
6
Fiscal Year
2010
Total Cost
$380,000
Indirect Cost
Name
Washington University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Craft, Clarissa S; Broekelmann, Thomas J; Mecham, Robert P (2018) Microfibril-associated glycoproteins MAGP-1 and MAGP-2 in disease. Matrix Biol 71-72:100-111
Mecham, Robert P (2018) Elastin in lung development and disease pathogenesis. Matrix Biol 73:6-20
Craft, Clarissa S (2015) MAGP1, the extracellular matrix, and metabolism. Adipocyte 4:60-4
Hubmacher, Dirk; Wang, Lauren W; Mecham, Robert P et al. (2015) Adamtsl2 deletion results in bronchial fibrillin microfibril accumulation and bronchial epithelial dysplasia--a novel mouse model providing insights into geleophysic dysplasia. Dis Model Mech 8:487-99
Mecham, Robert P; Gibson, Mark A (2015) The microfibril-associated glycoproteins (MAGPs) and the microfibrillar niche. Matrix Biol 47:13-33
Osei-Owusu, Patrick; Knutsen, Russell H; Kozel, Beth A et al. (2014) Altered reactivity of resistance vasculature contributes to hypertension in elastin insufficiency. Am J Physiol Heart Circ Physiol 306:H654-66
DeMarsilis, Antea J; Walji, Tezin A; Maedeker, Justine A et al. (2014) Elastin Insufficiency Predisposes Mice to Impaired Glucose Metabolism. J Mol Genet Med 8:
Craft, Clarissa S; Pietka, Terri A; Schappe, Timothy et al. (2014) The extracellular matrix protein MAGP1 supports thermogenesis and protects against obesity and diabetes through regulation of TGF-?. Diabetes 63:1920-32
Combs, Michelle D; Knutsen, Russell H; Broekelmann, Thomas J et al. (2013) Microfibril-associated glycoprotein 2 (MAGP2) loss of function has pleiotropic effects in vivo. J Biol Chem 288:28869-80
Cheng, Jeffrey K; Stoilov, Ivan; Mecham, Robert P et al. (2013) A fiber-based constitutive model predicts changes in amount and organization of matrix proteins with development and disease in the mouse aorta. Biomech Model Mechanobiol 12:497-510

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