The vascularization of engineered tissues is critical to the ultimate success of tissue engineering as an organ replacement therapy. The formation of new capillary vessels in vivo, or angiogenesis, also is linked to the pathogenesis of numerous diseases including cancer, and is regulated by local cues within the tissue microenvironment. The general goal of this RENEWAL proposal is to understand the mechanism by which local extracellular matrix (ECM) properties regulate capillary endothelial cell proliferation, gene expression, and capillary tube morphogenesis required in angiogenesis. The investigator has found that adhesion to ECM cooperates with growth factors to generate not only biochemical, but also mechanical signals that are important in driving capillary endothelial cell function. Studies from the past grant period demonstrated that ECM stiffness and composition could be used to regulate proliferation, gene expression, and capillary tube formation by modulating contractile tension generated by the actin cytoskeleton. In this proposal, the investigator proposes to further investigate the role of these mechanical and adhesive cues in regulating angiogenic behaviors.
Specific Aim 1 will be to investigate the role of ECM stiffness in regulating angiogenesis.
Specific Aim 2 will be to investigate the role of ECM peptide ligands in regulating angiogenesis.
Specific Aim 3 will be to investigate the role of spatial organization of the ECM in regulating angiogenesis. Together, these studies will define the mechanisms by which local structural and mechanical properties within ECM modulate endothelial cell function and capillary morphogenesis, and establish new strategies to promote angiogenesis in native ischemic tissues as well as in ex-vivo engineered tissues.

Public Health Relevance

The formation of new capillary vessels in vivo, or angiogenesis, is a rate limiting challenge in the development of engineered implants for organ replacement. Angiogenesis is also critical to many disease processes, including tumor growth and the establishment of atherosclerosis. This project is designed to develop a better understanding of how angiogenesis is regulated by local adhesive and mechanical cues, such that we may better design future approaches to control the growth of blood vessels in tissues.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB000262-13
Application #
8308302
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Hunziker, Rosemarie
Project Start
2000-02-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
13
Fiscal Year
2012
Total Cost
$342,352
Indirect Cost
$126,082
Name
University of Pennsylvania
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Lee, Esak; Song, H-H Greco; Chen, Christopher S (2016) Biomimetic on-a-chip platforms for studying cancer metastasis. Curr Opin Chem Eng 11:20-27
Sakar, Mahmut Selman; Eyckmans, Jeroen; Pieters, Roel et al. (2016) Cellular forces and matrix assembly coordinate fibrous tissue repair. Nat Commun 7:11036
Kutys, Matthew L; Chen, Christopher S (2016) Forces and mechanotransduction in 3D vascular biology. Curr Opin Cell Biol 42:73-79
Stevens, Kelly R; Miller, Jordan S; Blakely, Brandon L et al. (2015) Degradable hydrogels derived from PEG-diacrylamide for hepatic tissue engineering. J Biomed Mater Res A 103:3331-8
Baker, Brendon M; Trappmann, Britta; Wang, William Y et al. (2015) Cell-mediated fibre recruitment drives extracellular matrix mechanosensing in engineered fibrillar microenvironments. Nat Mater 14:1262-8
Bagley, Alexander F; Scherz-Shouval, Ruth; Galie, Peter A et al. (2015) Endothelial Thermotolerance Impairs Nanoparticle Transport in Tumors. Cancer Res 75:3255-67
Chaturvedi, Ritika R; Stevens, Kelly R; Solorzano, Ricardo D et al. (2015) Patterning vascular networks in vivo for tissue engineering applications. Tissue Eng Part C Methods 21:509-17
Bellas, Evangelia; Chen, Christopher S (2014) Forms, forces, and stem cell fate. Curr Opin Cell Biol 31:92-7
Breckenridge, Mark T; Desai, Ravi A; Yang, Michael T et al. (2014) Substrates with engineered step changes in rigidity induce traction force polarity and durotaxis. Cell Mol Bioeng 7:26-34
Rodriguez, Natalia M; Desai, Ravi A; Trappmann, Britta et al. (2014) Micropatterned multicolor dynamically adhesive substrates to control cell adhesion and multicellular organization. Langmuir 30:1327-35

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