While there have been vast improvements in vascular intervention to combat vascular occlusive diseases, restenosis (occlusion of the vessel) following the intervention remains a major clinical problem. The long-term goal of this proposal is to elucidate key factors that control changes in VSMC behavior associated with vascular occlusive disease and to design novel engineered biomaterials that can probe and control this behavior. While there have been extensive studies examining the biochemical effects of changes in the ECM, comparatively little attention has been focused on the effects of the biomechanical properties of the ECM on VSMC phenotype. Our preliminary data show that both (i) VSMC signaling induced by platelet-derived growth factor (PDGF) and (ii) VSMC directional migration are modulated significantly by substrate stiffness. We further find that substrate stiffness influences ECM deposition (collagen type I and III) and the production and secretion of matrix metalloproteinases (MMP) -2 and -9 that are known to degrade the matrix. Based on these observations, our central hypothesis is that the local mechanical environment has an essential role in vascular homeostasis and broad modulatory effects on the structural composition of ECM. We further hypothesize that initial injury promotes a VSMC phenotypic switch that subsequently contributes via positive feedback to the development of vascular occlusive diseases. To test these hypotheses, we will use a multi-scale approach to explore the effect of biomechanical environment on the molecular level, on cells, tissues, and tissue-engineered biomimetic model systems. We will use VSMCs and also native vessels from normal and atherosclerotic animals (Watanabe Hereditable Hyperlipidemic rabbit) to achieve clinical relevance.
Specific Aim 1 : Investigate the interrelationship of mechanical properties such as compliance and ECM and develop physiologically-relevant bioengineered model substrata.
Specific Aim 2 : Determine the effects of mechanical environment on VSMC phenotypic modulation on bioengineered substrata mimicking physiological and pathological conditions of blood vessels.
Specific Aim 3 : Characterize the effects of mechanical environment and biochemical changes on vessel behavior by tissue culture under in vivo-like conditions. Validation of our bioengineered substrata results in tissue cultures will yield valuable data, establishing a mechanistic foundation for elucidating the role of biomechanics on ECM remodeling and VSMC phenotype. The successful completion of these aims will lead to new strategies to control VSMC phenotype related to vascular occlusive disease by targeting regulation of ECM biomechanical properties of the vessel wall.

Public Health Relevance

This proposal seeks to understand the mechanisms that control the switching behavior of a major cell type in blood vessels that play a key role in the progression of atherosclerosis the leading cause of death in the Western world. Through researching these specific mechanisms, we have the potential to uncover novel therapeutic strategies to treat cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL072900-06S1
Application #
7919113
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Lundberg, Martha
Project Start
2003-04-01
Project End
2012-05-31
Budget Start
2009-09-01
Budget End
2010-05-31
Support Year
6
Fiscal Year
2009
Total Cost
$40,497
Indirect Cost
Name
Boston University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
049435266
City
Boston
State
MA
Country
United States
Zip Code
02215
Hartman, Christopher D; Isenberg, Brett C; Chua, Samantha G et al. (2017) Extracellular matrix type modulates cell migration on mechanical gradients. Exp Cell Res 359:361-366
Backman, Daniel E; LeSavage, Bauer L; Shah, Shivem B et al. (2017) A Robust Method to Generate Mechanically Anisotropic Vascular Smooth Muscle Cell Sheets for Vascular Tissue Engineering. Macromol Biosci 17:
Hartman, Christopher D; Isenberg, Brett C; Chua, Samantha G et al. (2016) Vascular smooth muscle cell durotaxis depends on extracellular matrix composition. Proc Natl Acad Sci U S A 113:11190-11195
Yao, Raphael; Wong, Joyce Y (2015) The effects of mechanical stimulation on controlling and maintaining marrow stromal cell differentiation into vascular smooth muscle cells. J Biomech Eng 137:020907
Sazonova, Olga V; Isenberg, Brett C; Herrmann, Jacob et al. (2015) Extracellular matrix presentation modulates vascular smooth muscle cell mechanotransduction. Matrix Biol 41:36-43
Park, Yoonjee C; Smith, Jared B; Pham, Tuan et al. (2014) Effect of PEG molecular weight on stability, T? contrast, cytotoxicity, and cellular uptake of superparamagnetic iron oxide nanoparticles (SPIONs). Colloids Surf B Biointerfaces 119:106-14
Gronau, Greta; Krishnaji, Sreevidhya T; Kinahan, Michelle E et al. (2012) A review of combined experimental and computational procedures for assessing biopolymer structure-process-property relationships. Biomaterials 33:8240-55
Kinahan, Michelle E; Filippidi, Emmanouela; Koster, Sarah et al. (2011) Tunable silk: using microfluidics to fabricate silk fibers with controllable properties. Biomacromolecules 12:1504-11
Williams, Corin; Brown, Xin Q; Bartolak-Suki, Erzsebet et al. (2011) The use of micropatterning to control smooth muscle myosin heavy chain expression and limit the response to transforming growth factor ?1 in vascular smooth muscle cells. Biomaterials 32:410-8
Sazonova, Olga V; Lee, Kristen L; Isenberg, Brett C et al. (2011) Cell-cell interactions mediate the response of vascular smooth muscle cells to substrate stiffness. Biophys J 101:622-30

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