Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 3, Pages 492-497Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1613855114
Keywords
tumor stiffness; endothelial cells; vascular permeability; glycation; extracellular matrix
Categories
Funding
- NIH [R01-HL127499, R01-CA163255, T32 GM008500, S10OD016191, S10OD018516]
- National Science Foundation (NSF) [1055502, 1435755]
- Cancer Research Society
- NSF Graduate Research Fellowship in Science, Technology, Engineering and Mathematics
- The Morgan Family Fellowship
- NSF Graduate Teaching Fellows in K-12 Education Fellowship
- New York State Stem Cell Science [CO29155]
- Directorate For Engineering
- Div Of Chem, Bioeng, Env, & Transp Sys [1741588] Funding Source: National Science Foundation
- Div Of Chem, Bioeng, Env, & Transp Sys
- Directorate For Engineering [1055502] Funding Source: National Science Foundation
- Div Of Civil, Mechanical, & Manufact Inn
- Directorate For Engineering [1435755, 1738345] Funding Source: National Science Foundation
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Tumor microvasculature tends to be malformed, more permeable, and more tortuous than vessels in healthy tissue, effects that have been largely attributed to up-regulated VEGF expression. However, tumor tissue tends to stiffen during solid tumor progression, and tissue stiffness is known to alter cell behaviors including proliferation, migration, and cell-cell adhesion, which are all requisite for angiogenesis. Using in vitro, in vivo, and ex ovo models, we investigated the effects of matrix stiffness on vessel growth and integrity during angiogenesis. Our data indicate that angiogenic outgrowth, invasion, and neovessel branching increase with matrix cross-linking. These effects are caused by increased matrix stiffness independent of matrix density, because increased matrix density results in decreased angiogenesis. Notably, matrix stiffness up-regulates matrix metalloproteinase (MMP) activity, and inhibiting MMPs significantly reduces angiogenic outgrowth in stiffer crosslinked gels. To investigate the functional significance of altered endothelial cell behavior in response to matrix stiffness, we measured endothelial cell barrier function on substrates mimicking the stiffness of healthy and tumor tissue. Our data indicate that barrier function is impaired and the localization of vascular endothelial cadherin is altered as function of matrix stiffness. These results demonstrate that matrix stiffness, separately from matrix density, can alter vascular growth and integrity, mimicking the changes that exist in tumor vasculature. These data suggest that therapeutically targeting tumor stiffness or the endothelial cell response to tumor stiffening may help restore vessel structure, minimizemetastasis, and aid in drug delivery.
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