In studying vessel wall development, the assumption has been that structural matrix proteins such as elastin are passive players in the process and do not influence cellular differentiation. This idea has recently been called into question by the characterization of supravalvular aortic stenosis (SVAS), an elastin associated disease in humans that indicates an intricate interplay between vessel wall mechanics and cellular maturation. SVAS was recently modeled in mice where it was found that elastin haplo insufficiency results in remarkable and unexpected changes in arterial wall structure, including thinner elastic lamellae, an increased number of smooth muscle cell layers, and, in the mouse, stable hypertension. Studies show that the vascular effects of elastin insufficiency occur early in development and result in a cardiovascular system that has adapted to the altered mechanical properties of the vessel wall. The objective of this proposal is to investigate how mutations in the elastin gene influence elastic fiber formation and blood vessel development. The hypothesis being investigated is that the developing cardiovascular system is highly adaptable and responsive to changes in hemodynamics brought about by altered vessel wall mechanics, as long as these changes occur within an as yet undefined developmental window. Elastin haplo insufficiency in mice provides an excellent model to investigate this hypothesis and to begin to understand how elastin mutations alter tissue function and development in humans with SVAS and other elastinopathies. The proposal has two objectives: To investigate how changes in elastin deposition and assembly influence vessel wall mechanics, the developmental recruitment of smooth muscle cells, and cardiovascular function; and to understand how elastin mutations alter elastic fiber assembly and tissue function that, in turn, lead to vascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL074138-04
Application #
7193404
Study Section
Pathobiochemistry Study Section (PBC)
Program Officer
Goldman, Stephen
Project Start
2004-04-01
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2009-03-31
Support Year
4
Fiscal Year
2007
Total Cost
$362,679
Indirect Cost
Name
Washington University
Department
Pediatrics
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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