The broad objective of this Bioengineering Research Grant is to study biomechanical interactions of angiogenic microvessels with the extracellular matrix (ECM) on the microscale level to develop a computational model of angiogenesis. Our previous work has lead to the hypothesis that the ECM structure adjacent to angiogenic microvessels and the mechanical loading conditions are potential determinants of angiogenic sprouting and neovessel growth and guidance. To test this hypothesis, we will evaluate angiogenesis in a collagen gel-based, 3- dimensional organ culture system of microvessels in the presence of altered mechanical boundary conditions and perturbed collagen fibril structure and gel properties. The interaction dynamics between the angiogenic sprouts and neovessels that form in this culture system with the adjacent collagen matrix and the overall tissue construct behavior will be modeled and analyzed using material point method (MPM). Experimental data of both microvessel behavior and collagen structure dynamics, gathered with advanced imaging techniques, will provide the framework and parameters for the modeling effort. Because of the importance of the local, microscale, interactions between the microvessel and the ECM, the model will emphasize these aspects. In addition to establishing a better understanding of the relationship between angiogenic vessels, the surrounding ECM structure, and the mechanics of the tissue undergoing angiogenesis, the project will provide the basis for improved control of tissue vascularization in both native tissues (e.g., repairing ischemic tissue) and tissue engineered constructs.

Public Health Relevance

The proposed research will elucidate fundamental aspects of the roles of mechanical forces and extracellular matrix structure in angiogenesis. The process of angiogenesis is an integral feature of wound healing and tumor metastastis. The results of this research will provide a mechanistic understanding of the interaction of angiogenic microvessels with the extracellular matrix, and provide guidelines for the design and development of vascularized tissue replacements.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL077683-08
Application #
8098813
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Gao, Yunling
Project Start
2004-01-01
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2013-06-30
Support Year
8
Fiscal Year
2011
Total Cost
$523,999
Indirect Cost
Name
University of Utah
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Utzinger, Urs; Baggett, Brenda; Weiss, Jeffrey A et al. (2015) Large-scale time series microscopy of neovessel growth during angiogenesis. Angiogenesis 18:219-32
Edgar, Lowell T; Maas, Steve A; Guilkey, James E et al. (2015) A coupled model of neovessel growth and matrix mechanics describes and predicts angiogenesis in vitro. Biomech Model Mechanobiol 14:767-82
Edgar, Lowell T; Hoying, James B; Weiss, Jeffrey A (2015) In Silico Investigation of Angiogenesis with Growth and Stress Generation Coupled to Local Extracellular Matrix Density. Ann Biomed Eng 43:1531-42
Edgar, Lowell T; Hoying, James B; Utzinger, Urs et al. (2014) Mechanical interaction of angiogenic microvessels with the extracellular matrix. J Biomech Eng 136:021001
Hoying, James B; Utzinger, Urs; Weiss, Jeffrey A (2014) Formation of microvascular networks: role of stromal interactions directing angiogenic growth. Microcirculation 21:278-89
Underwood, Clayton J; Edgar, Lowell T; Hoying, James B et al. (2014) Cell-generated traction forces and the resulting matrix deformation modulate microvascular alignment and growth during angiogenesis. Am J Physiol Heart Circ Physiol 307:H152-64
Edgar, Lowell T; Underwood, Clayton J; Guilkey, James E et al. (2014) Extracellular matrix density regulates the rate of neovessel growth and branching in sprouting angiogenesis. PLoS One 9:e85178
Krishnan, Laxminarayanan; Chang, Carlos C; Nunes, Sara S et al. (2013) Manipulating the microvasculature and its microenvironment. Crit Rev Biomed Eng 41:91-123
Edgar, Lowell T; Sibole, Scott C; Underwood, Clayton J et al. (2013) A computational model of in vitro angiogenesis based on extracellular matrix fibre orientation. Comput Methods Biomech Biomed Engin 16:790-801
Bal, Ufuk; Andresen, Volker; Baggett, Brenda et al. (2013) Intravital confocal and two-photon imaging of dual-color cells and extracellular matrix mimics. Microsc Microanal 19:201-12

Showing the most recent 10 out of 21 publications