The elastic properties of conducting vessels in vertebrates are determined, to a major extent, by the ratio of elastin to collagen. Under normal conditions, this ratio is dictated by the need to maintain the elastic modulus in a range that is best able to provide capacitance and pulse smoothing in a pulsatile circulatory system. This elastic modulus can change as a result of aging or disease through the loss of elastin or an increase in collagen. The consequences are a stiffening and dilation of the vessel and loss of its ability to dampen the pulsations in blood flow. Changes in blood flow and pressure result, with hypertension being a biomarker for altered vessel function. This proposal is organized around understanding the relationship between arterial stiffening and blood pressure changes.
Aim 1 will take advantage of mice where the elastin/collagen ratio has been reduced by inactivation of one copy of the elastin gene to study the relationship between arterial stiffening and the development of hypertension.
Aim 2 will employ conditional and inducible elastin transgenes to change the elastic properties of the vessel wall at different times to investigate the reversibility of stiffness-related hypertension.
Aim 3 will utilize gene expression profiling to identify individual genes, gene sets, and molecular pathways that change in response to vessel stiffness and alterations in blood pressure.
Aim 4 will pursue several treatment strategies that modulate blood pressure and alter vessel compliance.

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 #
5R01HL105314-02
Application #
8145303
Study Section
Special Emphasis Panel (ZHL1-CSR-W (S1))
Program Officer
Thrasher, Terry N
Project Start
2010-09-20
Project End
2014-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
2
Fiscal Year
2011
Total Cost
$375,500
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
Wagenseil, Jessica E (2018) Bio-chemo-mechanics of thoracic aortic aneurysms. Curr Opin Biomed Eng 5:50-57
Luo, Yongfeng; Li, Nan; Chen, Hui et al. (2018) Spatial and temporal changes in extracellular elastin and laminin distribution during lung alveolar development. Sci Rep 8:8334
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
Kabir, Ashraf Ul; Lee, Tae-Jin; Pan, Hua et al. (2018) Requisite endothelial reactivation and effective siRNA nanoparticle targeting of Etv2/Er71 in tumor angiogenesis. JCI Insight 3:
Turecamo, S E; Walji, T A; Broekelmann, T J et al. (2018) Contribution of metabolic disease to bone fragility in MAGP1-deficient mice. Matrix Biol 67:1-14
Gabriela Espinosa, Maria; Catalin Staiculescu, Marius; Kim, Jungsil et al. (2018) Elastic Fibers and Large Artery Mechanics in Animal Models of Development and Disease. J Biomech Eng 140:
Yamashiro, Yoshito; Thang, Bui Quoc; Shin, Seung Jae et al. (2018) Role of Thrombospondin-1 in Mechanotransduction and Development of Thoracic Aortic Aneurysm in Mouse and Humans. Circ Res 123:660-672
Kim, Jungsil; Staiculescu, Marius Catalin; Cocciolone, Austin J et al. (2017) Crosslinked elastic fibers are necessary for low energy loss in the ascending aorta. J Biomech 61:199-207
Halabi, Carmen M; Broekelmann, Thomas J; Lin, Michelle et al. (2017) Fibulin-4 is essential for maintaining arterial wall integrity in conduit but not muscular arteries. Sci Adv 3:e1602532

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